JOURNAL/nrgr/04.03/01300535-202602000-00045/figure1/v/2025-05-05T160104Z/r/image-tiff Neural stem cells (NSCs) have the potential for self-renewal and multidirectional differentiation, and their transplantation has achieved good efficacy in a variety of diseases. However, only 1%-10% of transplanted NSCs survive in the ischemic and hypoxic microenvironment of posthemorrhagic hydrocephalus. Sox2 is an important factor for NSCs to maintain proliferation. Therefore, Sox2-overexpressing NSCs (NSCSox2) may be more successful in improving neurological dysfunction after posthemorrhagic hydrocephalus. In this study, human NSCSox2 was transplanted into a posthemorrhagic hydrocephalus mouse model, and retinoic acid was administered to further promote NSC differentiation. The results showed that NSCSox2 attenuated the ventricular enlargement caused by posthemorrhagic hydrocephalus and improved neurological function. NSCSox2 also promoted nerve regeneration, inhibited neuroinflammation and promoted M2 polarization (anti-inflammatory phenotype), thereby reducing cerebrospinal fluid secretion in choroid plexus. These findings suggest that NSCSox2 rescued ventricular enlargement and neurological dysfunction induced by posthemorrhagic hydrocephalus through neural regeneration and modulation of inflammation.

Adult hippocampal neurogenesis is linked to memory formation in the adult brain, with new neurons in the hippocampus exhibiting greater plasticity during their immature stages compared to mature neurons. Abnormal adult hippocampal neurogenesis is closely associated with cognitive impairment in central nervous system diseases. Targeting and regulating adult hippocampal neurogenesis have been shown to improve cognitive deficits. This review aims to expand the current understanding and prospects of targeting neurogenesis in the treatment of cognitive impairment. Recent research indicates the presence of abnormalities in AHN in several diseases associated with cognitive impairment, including cerebrovascular diseases, Alzheimer's disease, aging-related conditions, and issues related to anesthesia and surgery. The role of these abnormalities in the cognitive deficits caused by these diseases has been widely recognized, and targeting AHN is considered a promising approach for treating cognitive impairment. However, the underlying mechanisms of this role are not yet fully understood, and the effectiveness of targeting abnormal adult hippocampal neurogenesis for treatment remains limited, with a need for further development of treatment methods and detection techniques. By reviewing recent studies, we classify the potential mechanisms of adult hippocampal neurogenesis abnormalities into four categories: immunity, energy metabolism, aging, and pathological states. In immunity-related mechanisms, abnormalities in meningeal, brain, and peripheral immunity can disrupt normal adult hippocampal neurogenesis. Lipid metabolism and mitochondrial function disorders are significant energy metabolism factors that lead to abnormal adult hippocampal neurogenesis. During aging, the inflammatory state of the neurogenic niche and the expression of aging-related microRNAs contribute to reduced adult hippocampal neurogenesis and cognitive impairment in older adult patients. Pathological states of the body and emotional disorders may also result in abnormal adult hippocampal neurogenesis. Among the current strategies used to enhance this form of neurogenesis, physical therapies such as exercise, transcutaneous electrical nerve stimulation, and enriched environments have proven effective. Dietary interventions, including energy intake restriction and nutrient optimization, have shown efficacy in both basic research and clinical trials. However, drug treatments, such as antidepressants and stem cell therapy, are primarily reported in basic research, with limited clinical application. The relationship between abnormal adult hippocampal neurogenesis and cognitive impairment has garnered widespread attention, and targeting the former may be an important strategy for treating the latter. However, the mechanisms underlying abnormal adult hippocampal neurogenesis remain unclear, and treatments are lacking. This highlights the need for greater focus on translating research findings into clinical practice.

Ischemic stroke is a significant global health crisis, frequently resulting in disability or death, with limited therapeutic interventions available. Although various intrinsic reparative processes are initiated within the ischemic brain, these mechanisms are often insufficient to restore neuronal functionality. This has led to intensive investigation into the use of exogenous stem cells as a potential therapeutic option. This comprehensive review outlines the ontogeny and mechanisms of activation of endogenous neural stem cells within the adult brain following ischemic events, with focus on the impact of stem cell-based therapies on neural stem cells. Exogenous stem cells have been shown to enhance the proliferation of endogenous neural stem cells via direct cell-to-cell contact and through the secretion of growth factors and exosomes. Additionally, implanted stem cells may recruit host stem cells from their niches to the infarct area by establishing so-called "biobridges." Furthermore, xenogeneic and allogeneic stem cells can modify the microenvironment of the infarcted brain tissue through immunomodulatory and angiogenic effects, thereby supporting endogenous neuroregeneration. Given the convergence of regulatory pathways between exogenous and endogenous stem cells and the necessity for a supportive microenvironment, we discuss three strategies to simultaneously enhance the therapeutic efficacy of both cell types. These approaches include: (1) co-administration of various growth factors and pharmacological agents alongside stem cell transplantation to reduce stem cell apoptosis; (2) synergistic administration of stem cells and their exosomes to amplify paracrine effects; and (3) integration of stem cells within hydrogels, which provide a protective scaffold for the implanted cells while facilitating the regeneration of neural tissue and the reconstitution of neural circuits. This comprehensive review highlights the interactions and shared regulatory mechanisms between endogenous neural stem cells and exogenously implanted stem cells and may offer new insights for improving the efficacy of stem cell-based therapies in the treatment of ischemic stroke.

JOURNAL/nrgr/04.03/01300535-202512000-00029/figure1/v/2025-01-31T122243Z/r/image-tiff Secondary injury following spinal cord injury is primarily characterized by a complex inflammatory response, with resident microglia and infiltrating macrophages playing pivotal roles. While previous studies have grouped these two cell types together based on similarities in structure and function, an increasing number of studies have demonstrated that microglia and macrophages exhibit differences in structure and function and have different effects on disease processes. In this study, we used single-cell RNA sequencing and spatial transcriptomics to identify the distinct evolutionary paths of microglia and macrophages following spinal cord injury. Our results showed that microglia were activated to a pro-inflammatory phenotype immediately after spinal cord injury, gradually transforming to an anti-inflammatory steady state phenotype as the disease progressed. Regarding macrophages, our findings highlighted abundant communication with other cells, including fibroblasts and neurons. Both pro-inflammatory and neuroprotective effects of macrophages were also identified; the pro-inflammatory effect may be related to integrin β2 ( Itgb2 ) and the neuroprotective effect may be related to the oncostatin M pathway. These findings were validated by in vivo experiments. This research underscores differences in the cellular dynamics of microglia and macrophages following spinal cord injury, and may offer new perspectives on inflammatory mechanisms and potential therapeutic targets.

JOURNAL/nrgr/04.03/01300535-202510000-00027/figure1/v/2024-11-26T163120Z/r/image-tiff Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer's disease. Adult hippocampal neurogenesis is reduced in patients with Alzheimer's disease. Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer's disease. However, the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer's disease are poorly understood. Recently, regulator of G protein signaling 6 (RGS6) was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice. Here, we generated novel RGS6 fl/fl ; APP SWE mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer's disease mouse model. We found that voluntary running in APP SWE mice restored their hippocampal cognitive impairments to that of control mice. This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells, which also abolished running-mediated increases in adult hippocampal neurogenesis. Adult hippocampal neurogenesis was reduced in sedentary APP SWE mice versus control mice, with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells. RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer's disease with significant loss of these RGS6-expressing neurons. Thus, RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP SWE mice, identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer's disease.

Alzheimer's disease is a common neurodegenerative disorder in older adults. Despite its prevalence, its pathogenesis remains unclear. In addition to the most widely accepted causes, which include excessive amyloid-beta aggregation, tau hyperphosphorylation, and deficiency of the neurotransmitter acetylcholine, numerous studies have shown that the dopaminergic system is also closely associated with the occurrence and development of this condition. Dopamine is a crucial catecholaminergic neurotransmitter in the human body. Dopamine-associated treatments, such as drugs that target dopamine receptor D and dopamine analogs, can improve cognitive function and alleviate psychiatric symptoms as well as ameliorate other clinical manifestations. However, therapeutics targeting the dopaminergic system are associated with various adverse reactions, such as addiction and exacerbation of cognitive impairment. This review summarizes the role of the dopaminergic system in the pathology of Alzheimer's disease, focusing on currently available dopamine-based therapies for this disorder and the common side effects associated with dopamine-related drugs. The aim of this review is to provide insights into the potential connections between the dopaminergic system and Alzheimer's disease, thus helping to clarify the mechanisms underlying the condition and exploring more effective therapeutic options.

JOURNAL/nrgr/04.03/01300535-202509000-00031/figure1/v/2024-11-05T132919Z/r/image-tiff A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease. Consequently, enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression. Nonetheless, non-pharmacological interventions aimed at inducing adult neurogenesis are currently limited. Although individual non-pharmacological interventions, such as aerobic exercise, acousto-optic stimulation, and olfactory stimulation, have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer's disease, the therapeutic effect of a strategy that combines these interventions has not been fully explored. In this study, we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2-8 months. Amyloid deposition became evident at 4 months, while neurogenesis declined by 6 months, further deteriorating as the disease progressed. However, following a 4-week multifactor stimulation protocol, which encompassed treadmill running (46 min/d, 10 m/min, 6 days per week), 40 Hz acousto-optic stimulation (1 hour/day, 6 days/week), and olfactory stimulation (1 hour/day, 6 days/week), we found a significant increase in the number of newborn cells (5'-bromo-2'-deoxyuridine-positive cells), immature neurons (doublecortin-positive cells), newborn immature neurons (5'-bromo-2'-deoxyuridine-positive/doublecortin-positive cells), and newborn astrocytes (5'-bromo-2'-deoxyuridine-positive/glial fibrillary acidic protein-positive cells). Additionally, the amyloid-beta load in the hippocampus decreased. These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice. Furthermore, cognitive abilities were improved, and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation, as evidenced by Morris water maze, novel object recognition, forced swimming test, and tail suspension test results. Notably, the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2 weeks after treatment cessation. At the molecular level, multifactor stimulation upregulated the expression of neuron-related proteins (NeuN, doublecortin, postsynaptic density protein-95, and synaptophysin), anti-apoptosis-related proteins (Bcl-2 and PARP), and an autophagy-associated protein (LC3B), while decreasing the expression of apoptosis-related proteins (BAX and caspase-9), in the hippocampus of amyloid precursor protein/presenilin 1 mice. These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways. Furthermore, serum metabolomics analysis indicated that multifactor stimulation regulated differentially expressed metabolites associated with cell apoptosis, oxidative damage, and cognition. Collectively, these findings suggest that multifactor stimulation is a novel non-invasive approach for the prevention and treatment of Alzheimer's disease.

Phosphodiesterase 9 (PDE9) plays a critical role in synaptic plasticity and cognitive function by modulating cyclic GMP (cGMP). Many reports have shown that PDE9 inhibition improves cognitive function and synaptic plasticity in rodents. Several studies have found that the NO/cGMP/PKG pathway is downregulated in patients with Alzheimer's disease (AD) or dementia with Lewy bodies (DLB) and in older individuals. A PDE9 inhibitor could therefore be a potential therapeutic approach for improving cognitive dysfunction in dementia, including in AD and DLB. We previously discovered a novel PDE9 inhibitor, irsenontrine (E2027). In the current study, irsenontrine showed highly selective affinity for PDE9 with more than 1800-fold selectivity over other PDEs. Irsenontrine maleate significantly increased intracellular cGMP levels in rat cortical primary neurons, and phosphorylation of AMPA receptor subunit GluA1 was induced following cGMP elevation. Oral administration of irsenontrine significantly upregulated cGMP levels in the hippocampus and cerebrospinal fluid (CSF) of naïve rats, and a novel object recognition test showed that irsenontrine administration also significantly improved learning and memory. The effects of irsenontrine were confirmed in rats treated with Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME), a model of learning and memory impairment due to downregulation of the cGMP pathway. l-NAME downregulated cGMP in the CSF and hippocampus and impaired novel object recognition, but oral administration of irsenontrine clearly attenuated these phenotypes. These results indicate that irsenontrine improves learning and memory via the elevation of cGMP levels, and they strongly suggest that irsenontrine could be a novel therapeutic approach against cognitive dysfunction.

Zinc deficiency during adolescence poses a significant yet understudied risk to brain development. The study aimed to investigate the effects of marginal zinc deficiency during adolescence on emotion and cognition, morphological changes and neuronal arrangement of hippocampus and cortical, and proBDNF, mBDNF and TrkB expression levels. The emotion was assessed using the open-field test and three-chamber test. Additionally, cognition was evaluated using the Morris water maze test and novel object recognition test. Morphological changes were evaluated using H&E staining, while Nissl staining was employed to analyze neuronal arrangement. Additionally, proBDNF, mBDNF and TrkB expression levels were quantified by western blot. The results showed that adolescent marginal zinc deficiency induced risk-taking behavior, impaired spatial learning and memory, and caused new object recognition deficits without affecting sociability. Moreover, marginal zinc deficiency critically disrupted hippocampal and cortical development, and aberrant neuronal arrangement. The expression levels of BDNF for both form states were not statistically significant upregulation in marginal zinc deficiency mice compared to controls, along with significantly increased TrkB expression. These findings suggested that adolescent marginal zinc deficiency increased the expression of BDNF and TrkB, as well as abnormal hippocampal and cortical development. These alterations may explain the observed abnormal behavior, including risk-taking behavior, impaired spatial learning and memory, and new object recognition decay.

The functional and structural integrity of the blood-brain barrier is crucial in maintaining homeostasis in the brain microenvironment; however, the molecular mechanisms underlying the formation and function of the blood-brain barrier remain poorly understood. The major facilitator superfamily domain containing 2A has been identified as a key regulator of blood-brain barrier function. It plays a critical role in promoting and maintaining the formation and functional stability of the blood-brain barrier, in addition to the transport of lipids, such as docosahexaenoic acid, across the blood-brain barrier. Furthermore, an increasing number of studies have suggested that major facilitator superfamily domain containing 2A is involved in the molecular mechanisms of blood-brain barrier dysfunction in a variety of neurological diseases; however, little is known regarding the mechanisms by which major facilitator superfamily domain containing 2A affects the blood-brain barrier. This paper provides a comprehensive and systematic review of the close relationship between major facilitator superfamily domain containing 2A proteins and the blood-brain barrier, including their basic structures and functions, cross-linking between major facilitator superfamily domain containing 2A and the blood-brain barrier, and the in-depth studies on lipid transport and the regulation of blood-brain barrier permeability. This comprehensive systematic review contributes to an in-depth understanding of the important role of major facilitator superfamily domain containing 2A proteins in maintaining the structure and function of the blood-brain barrier and the research progress to date. This will not only help to elucidate the pathogenesis of neurological diseases, improve the accuracy of laboratory diagnosis, and optimize clinical treatment strategies, but it may also play an important role in prognostic monitoring. In addition, the effects of major facilitator superfamily domain containing 2A on blood-brain barrier leakage in various diseases and the research progress on cross-blood-brain barrier drug delivery are summarized. This review may contribute to the development of new approaches for the treatment of neurological diseases.

Alzheimer's disease (AD) and vascular dementia (VaD) are two prevalent forms of dementia. VaD is linked to cerebrovascular lesions, such as those from white matter ischemia and chronic cerebral hypoperfusion, which can also occur in AD. Nitric oxide (NO) regulates cerebral blood flow (CBF) in the central nervous system. Memantine is an NMDA receptor antagonist approved for AD treatment. This study investigated the efficacy and molecular mechanism of MN-08, a novel memantine nitrate, in one VaD model (2VO) and two AD models (APP/PS1 mice and Aβ1-42-induced mice). MN-08 increased CBF, ameliorated cognitive and memory functions in VaD and AD, and was more effective than memantine. MN-08 increased the survival rate of CA1 neurons and mitigated white matter lesions and axonal damage. Moreover, MN-08 protected neurons from OGD-induced loss and promoted axonal outgrowth in the hippocampus by upregulating phosphorylated Akt (p-Akt), glycogen synthase kinase-3β (p-GSK3β), and high-molecular-weight neurofilaments (p-NFH). The beneficial effects of MN-08 were attenuated by carboxy-PTIO, a potent NO scavenger, suggesting that MN-08-derived NO may alleviate cognitive impairment from cerebral hypoperfusion. Taken together, our studies demonstrate that MN-08 is a promising therapeutic agent for the treatment of dementia including VaD and AD.

Attention-deficit hyperactivity disorder (ADHD) is a prevalent psychiatric disorder with high heritability, while its etiology and pathophysiology remain unclear. Med23 is a subunit of the Mediator complex, a key regulator of gene expression by linking transcription factors to RNA polymerase II. The mutations of Med23 are associated with several brain diseases including microcephaly, epilepsy and intellectual disability, but its biological roles in brain development and possible behavioral consequence have not been explored in the animal model. In this study, Emx1-Cre mice were used to generate Med23 conditional knockout (Med23 CKO) mice that showed severe hypoplasia of the dentate gyrus (DG) with malformation of the dendritic tree and spines along with impaired short-term synaptic plasticity. Interestingly, Med23 CKO mice exhibited ADHD-like behaviors as shown by hyperactivity, inattention and impulsivity, as well as impaired sensory gating and working memory. Importantly, methylphenidate (MPH), a common drug for ADHD ameliorated these deficits in the CKO mice. Furthermore, we also revealed that the impaired synaptic plasticity was partially restored by MPH in an N-methyl-d-aspartate (NMDA) receptor-dependent way. Collectively, our data demonstrate Med23 deficiency causes DG malformation and ADHD-like behaviors, suggesting a novel mechanism underlying relevant brain diseases.

Aging is characterized by a deterioration of stem cell function, but the feasibility of replenishing these cells to counteract aging remains poorly defined. Our study addresses this gap by developing senescence (seno)-resistant human mesenchymal progenitor cells (SRCs), genetically fortified to enhance cellular resilience. In a 44-week trial, we intravenously delivered SRCs to aged macaques, noting a systemic reduction in aging indicators, such as cellular senescence, chronic inflammation, and tissue degeneration, without any detected adverse effects. Notably, SRC treatment enhanced brain architecture and cognitive function and alleviated the reproductive system decline. The restorative effects of SRCs are partly attributed to their exosomes, which combat cellular senescence. This study provides initial evidence that genetically modified human mesenchymal progenitors can slow primate aging, highlighting the therapeutic potential of regenerative approaches in combating age-related health decline.

The number of neurons in the developing brain is greater than typically found in adulthood, and the brain possesses delicate mechanisms to induce the death of excess cells and refine neural circuitry. The correct tuning between the processes of neuronal death and survival generates a mature and functional brain in its complexity and plastic capacity. Epilepsy is a highly prevalent neurological condition worldwide, including among young individuals. However, exposure to the main treatment approaches, the long-term use of Antiseizure Medication (ASM), during the critical period of development can induce a series of changes in this delicate balance. Acting by various mechanisms of action, ASMs may induce an increase in neuronal death, something that translates into deleterious neuropsychiatric effects in adulthood. Several investigations conducted in recent years have brought to light new aspects related to this dynamic, yet many questions, such as the cellular mechanisms of death and the pathophysiology of late effects, still have unresolved elements. In this review, we aimed to explore the mechanisms of action of the most widely used ASMs in the treatment of neonatal epilepsy, the broad aspects of neuronal death in the developing brain and the repercussions of this death and other effects in adulthood. We review the evidence indicating a relationship between exposure to ASMs and the manifestation of associated psychiatric comorbidities in adulthood and discuss some possible mechanisms underlying the induction of this process by morphological and physiological changes in the related behaviors.

Poor vascular function and reduced nitric oxide (NO)-bioavailability have been recognized to be involved in aging and Alzheimer's Disease (AD). A non-pharmacological treatment that is gaining clinical interest in the context of vascular function is dietary inorganic nitrate (NO3-) supplementation which increases NO-bioavailability through the NO3- -nitrite (NO2-) - NO pathway. This treatment has been demonstrated to improve vascular function in several clinical populations, but no study has investigated the effects in individuals with AD. Therefore, changes in plasma NO3- and NO2- and vascular responsiveness (hyperemic response to single-passive leg movement (ΔPLM)) were measured in individuals with AD (n = 10, 76 ± 9 years), healthy elderly (OLD, n = 10, 75 ± 6 years), and young individuals (YN, n = 10, 25 ± 4 years) before (T0) and hourly for 4 h (T1, T2, T3, and T4) after ingestion of either NO3--rich beetroot juice (BR) or a placebo (PLA). No changes in NO3- and NO2-, nor ΔPLM were detected in any group following PLA intake. Plasma NO3- and NO2- increased significantly in all three groups at T1 (p < 0.001) and remained elevated for the rest of the trial. The same trend was found in ΔPLM, which significantly increased in all three groups over the time (p < 0.001). However, AD exhibited significantly lower ΔPLM values at any time point compared to YN (p < 0.001) and OLD (p < 0.001). These data suggest that AD-individuals included in this study were able to reduce NO3- to NO2- and to increase NO-mediated vascular responsiveness as non-AD-individuals. Other mechanisms, beyond NO-bioavailability, may be involved in vascular dysfunction in patients with AD. This research suggests that an acute administration of inorganic nitrate is not enough to revert chronically adapted vascular properties and completely restore vascular responsiveness in AD.

Patients with atrial fibrillation (AF) and dementia face unique challenges in stroke prevention, particularly in selecting appropriate anticoagulation therapy. Direct oral anticoagulants (DOACs) effectively reduce stroke and embolism risks, but evidence comparing their effectiveness and safety in this population remains limited.

This retrospective, population-based cohort study used data from Taiwan's National Health Insurance Research Database to evaluate outcomes of four DOACs (dabigatran, apixaban, edoxaban, and rivaroxaban) in AF patients with dementia aged 50 years or older. We used propensity score matching to balance baseline characteristics across six DOAC comparison pairs.

Dabigatran demonstrated superior outcomes, reducing the composite risk of ischemic stroke, acute myocardial infarction, intracranial hemorrhage, major bleeding, and all-cause mortality compared to apixaban (hazard ratio [HR], 0.82; 95 % confidence interval [CI], 0.73-0.92), edoxaban (HR, 0.81; 95 % CI, 0.71-0.92), and rivaroxaban (HR, 0.82; 95 % CI, 0.73-0.91). It also showed lower risks of intracranial hemorrhage and all-cause mortality. Sensitivity analyses excluding patients with nasogastric tubes or severe renal impairment showed smaller differences in overall outcomes but maintained dabigatran's advantage in reducing intracranial hemorrhage risk.

This study demonstrates the need for tailored anticoagulation strategies in this vulnerable population, with dabigatran emerging as a potentially safer and more effective option for stroke prevention in AF patients with dementia. Future research should examine individual DOAC effects across diverse clinical settings to optimize treatment outcomes.

Platelets play a vital role in preventing haemorrhage through haemostasis, but complications arise when platelets become overly reactive, leading to pathophysiology such as atherothrombosis. Elevated haemostatic markers are linked to dementia and predict its onset in long-term studies. Despite epidemiological evidence, the mechanism linking haemostasis with early brain pathophysiology remains unclear. Here, we aimed to determine whether a mechanistic association exists between platelet function and cerebral neurovascular function in 52 healthy mid- to older-age adults. To do this, we combined, for the first time, magnetic resonance imaging of cerebral neurovascular function, peripheral vascular physiology and in vitro platelet assaying. We show an association between platelet reactivity and cerebral neurovascular function that is both independent of vascular reactivity and mechanistically specific: Distinct platelet signalling mechanisms (ADP, collagen-related peptide, thrombin receptor activator peptide 6) were associated with different physiological components of the haemodynamic response to neuronal (visual) stimulation (full-width half-maximum, time to peak, area under the curve), an association that was not mediated by peripheral vascular effects. This finding challenges the previous belief that systemic vascular health determines the vascular component of cerebral neurovascular function, highlighting a specific link between circulating platelets and the neurovascular unit. Because altered cerebral neurovascular function marks the initial stages of neurodegenerative pathophysiology, understanding this novel association is now imperative, with the potential to lead to a significant advancement in our comprehension of early dementia pathophysiology. KEY POINTS: Haemostasis (platelet function) has been linked to the early stages of dementia, but the precise mechanisms are not well understood. This study considers whether a causal mechanism exists through atherothrombotic effects on the vasculature which can in turn affect brain health, or through platelet-specific interactions with brain physiology. Here, we show that elevated platelet reactivity is associated with blunted (delayed, shorter and smaller) cerebral blood flow responses to neuronal activation in healthy middle-aged and older adults. However, the association between platelet reactivity and cerebral neurovascular function was not mediated by systemic vascular reactivity. This finding challenges the previous belief that systemic vascular health determines the vascular component of cerebral neurovascular function, highlighting a specific link between circulating platelets and the neurovascular unit in early dementia pathophysiology.

Tanycytes, specialized ependymal cells located in the hypothalamus, play a crucial role in the generation of new neurons that contribute to the neural circuits responsible for regulating the systemic energy balance. The precise coordination of the gene networks controlling neurogenesis in naive and mature tanycytes is essential for maintaining homeostasis in adulthood. However, our understanding of the molecular mechanisms and signaling pathways that govern the proliferation and differentiation of tanycytes into neurons remains limited. This article aims to review the recent advancements in research into the mechanisms and functions of tanycyte-derived neurogenesis. Studies employing lineage-tracing techniques have revealed that the neurogenesis specifically originating from tanycytes in the hypothalamus has a compensatory role in neuronal loss and helps maintain energy homeostasis during metabolic diseases. Intriguingly, metabolic disorders are considered early biomarkers of Alzheimer's disease. Furthermore, the neurogenic potential of tanycytes and the state of newborn neurons derived from tanycytes heavily depend on the maintenance of mild microenvironments, which may be disrupted in Alzheimer's disease due to the impaired blood-brain barrier function. However, the specific alterations and regulatory mechanisms governing tanycyte-derived neurogenesis in Alzheimer's disease remain unclear. Accumulating evidence suggests that tanycyte-derived neurogenesis might be impaired in Alzheimer's disease, exacerbating neurodegeneration. Confirming this hypothesis, however, poses a challenge because of the lack of long-term tracing and nucleus-specific analyses of newborn neurons in the hypothalamus of patients with Alzheimer's disease. Further research into the molecular mechanisms underlying tanycyte-derived neurogenesis holds promise for identifying small molecules capable of restoring tanycyte proliferation in neurodegenerative diseases. This line of investigation could provide valuable insights into potential therapeutic strategies for Alzheimer's disease and related conditions.

Alzheimer's Disease (AD) is an incurable and debilitating progressive, neurodegenerative disorder which is the leading cause of dementia worldwide. Neuropathologically, AD is characterized by the accumulation of Aβ amyloid plaques in the microenvironment of brain cells and neurovascular walls, chronic neuroinflammation, resulting in neuronal and synaptic loss, myelin and axonal failure, as well as significant reduction in adult hippocampal neurogenesis. The hippocampal formation is particularly vulnerable to this degenerative process, due to early dysfunction of the cholinergic circuit. Neurotrophic factors consist major regulatory molecules and their decline in AD is considered as an important cause of disease onset and progression. Novel pharmacological approaches are targeting the downstream pathways controlled by neurotrophins, such as nerve growth factor (NGF) receptors, TrkA and p75NTR, which enhance hippocampal neurogenic capacity and neuroprotective mechanisms, and potentially counteract the neurotoxic effects of amyloid deposition. BNN27 is a non-toxic, newly developed 17-spiro-steroid analog, penetrating the blood-brain-barrier (BBB) and mimicking the neuroprotective effects of NGF, acting as selective activator of its receptors, both TrkA and p75NTR, thus promoting survival of various neuronal cell types. Our present research aims at determining whether and which aspects of the AD-related pathology, BNN27 is able to alleviate, exploring the cellular and molecular AD components and link these changes with improvements in the cognitive performance of an animal AD model, the 5xFAD mice. Our results clearly indicate that BNN27 administration significantly reduced amyloid-β load in whole brain of the animals, enhanced adult hippocampal neurogenesis, restored cholinergic function and synaptogenesis, reducing inflammatory activation and leading to significant restoration of cognitive functions. BNN27 may represent a new lead multimodal molecule with neuroprotective, neurogenic and anti-neuroinflammatory actions for developing druggable anti-Alzheimeric agents. Proteomics data are available via ProteomeXchange with the identifier PXD044699.

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Triggering receptor expressed on myeloid cells-2 (TREM2) mainly expressed on microglia in the brain, and its mutations can increase the risk of Alzheimer's disease (AD). Upregulation or activation of TREM2 has been found to ameliorate several pathological features of AD, such as the reduction of amyloid beta (Aβ) plaques and tau hyperphosphorylation. However, the effects of TREM2 on neurogenesis are little understood. Here, we aimed to investigate the effects of TREM2 on hippocampal neurogenesis associated with microglial M2 polarization in APP/PS1 mice. Lentivirus vectors were used to interfere with the expression of TREM2 on microglia in the hippocampus of APP/PS1 mice and BV2 cells. The supernatant was collected from BV2 cells as a conditioned medium (CM) to culture neural stem cells (NSCs) in vitro. Upregulation of TREM2 partially salvaged the proliferation of NSCs and the decrease of the number of immature/mature neurons in the hippocampus of APP/PS1 mice, which was accompanied by an improvement in cognitive ability. Furthermore, upregulation of TREM2 increased the M2 microglia marker CD206, brain-derived neurotrophic factor (BDNF), and anti-inflammatory factors, while decreased the M1 microglia markers CD16/32 and CD86 and pro-inflammatory factors in vivo and in vitro. Importantly, the upregulation of TREM2 also led to a significant increase in the phosphorylation of PI3K and Akt. In vitro, treatment with LY294002, a PI3K inhibitor, abolished the beneficial effects of TREM2 on shifting microglia from M1 to M2 and the proliferation and differentiation of NSCs. Taken together, these findings indicated that upregulation of TREM2 activated the PI3K/Akt signaling pathway to promote microglial M2 polarization and led to the secretion of more BDNF, accompanied by an improved hippocampal neurogenesis and spatial cognitive function in APP/PS1 mice. Thus, TREM2 might be a promising target for the treatment of neurodegenerative disease.

Proteostasis (protein homeostasis) refers to the general biological process that maintains the proper balance between the synthesis of proteins, their folding, trafficking, and degradation. It ensures proteins are functional, locally distributed, and appropriately folded inside cells. Genetic information enclosed in mRNA is translated into proteins. To ensure newly synthesized proteins take on the exact three-dimensional conformation, molecular chaperones assist in proper folding. Misfolded proteins can be refolded or targeted for elimination to stop aggregation. Cells utilize different degradation pathways, for instance, the ubiquitin-proteasome system, the autophagy-lysosome pathway, and the unfolded protein response, to degrade unwanted or damaged proteins. Quality control systems of the cell monitor the folding of proteins. These checkpoint mechanisms are aimed at degrading or refolding misfolded or damaged proteins. Under stress response pathways, such as heat shock response and unfolded protein response, which are triggered under conditions that perturb proteostasis, the capacity for folding is increased, and degradation pathways are activated to help cells handle stressful conditions. The deregulation of proteostasis is implicated in a variety of illnesses, comprising cancer, metabolic diseases, cardiovascular diseases, and neurological disorders. Therapeutic strategies with a deeper insight into the mechanism of proteostasis are crucial for the treatment of illnesses linked with proteostasis and to support cellular health. Thus, proteostasis is required not only for the maintenance of cellular homeostasis and function but also for proper protein function and prevention of injurious protein aggregation. In this review, we have covered the concept of proteostasis, its mechanism, and how disruptions to it can result in a number of disorders.

Natural toxins produced by various living organisms pose significant risks to health, food security, and environmental balance through inhalation, ingestion, and other exposure routes. This review focuses on the ameliorative effects of different Achillea species, which comprise over 130 perennial herbs known for their therapeutic properties. A systematic examination of data from Scopus, PubMed, and Web of Science was conducted, encompassing various studies without date restrictions, ensuring a comprehensive selection of articles based on full-text availability. The results of this study indicate that Achillea millefolium exhibits anti-hyperglycemic and anti-hyperlipidemic properties, enhances collagen proliferation regulation, suppresses inflammatory responses, and displays significant antioxidant activity. Similarly, A. wilhelmsii has been shown to have hepatoprotective effects, as evidenced by reduced malondialdehyde levels and increased total thiol concentrations. A. fragrantissima has also been demonstrated to have cardioprotective effects, with a decrease in inflammatory markers and edema levels. The protective benefits of other species within the Achillea genus extend to various toxins. This comprehensive review underscores the potential of Achillea species as natural remedies for combating toxicities and promoting health.

Alzheimer's disease (AD) is a predominant neurodegenerative disorder worldwide, with epileptic seizures being a common comorbidity that can exacerbate cognitive deterioration in affected individuals, thus highlighting the importance of early therapeutic intervention. It is determined that deletion of Ms4a4a, an AD-associated gene, exacerbates seizures in amyloid β (Aβ)-driven AD mouse model. MS4A4A is significantly upregulated in brain lesions in patients with epilepsy. Single-cell sequencing reveals that MS4A4A is highly expressed in microglia within these lesions, linked to enhanced phagocytic activity. Mechanistic investigation delineates that deletion of Ms4a4a impairs microglial phagocytosis, accompanied by diminished calcium influx and disruptions in mitochondrial metabolic fitness. The cytosolic fragment of Ms4a4a is anchored to the cytoskeletal components, supporting its critical role in mediating phagocytosis. Induction of Ms4a4a through central delivery of LNP-Il4 alleviates seizure conditions. Collectively, these findings identify Ms4a4a as a potential therapeutic target for managing seizures in AD treatment.

Irisin is a myokine that is generated by cleavage of the membrane protein fibronectin type III domain-containing protein 5 (FNDC5) in response to physical exercise. Studies reveal that irisin/FNDC5 has neuroprotective functions against Alzheimer's disease, the most common form of dementia in the elderly, by improving cognitive function and reducing amyloid-β and tau pathologies as well as neuroinflammation in cell culture or animal models of Alzheimer's disease. Although current and ongoing studies on irisin/FNDC5 show promising results, further mechanistic studies are required to clarify its potential as a meaningful therapeutic target for alleviating Alzheimer's disease. We recently found that irisin treatment reduces amyloid-β pathology by increasing the activity/levels of amyloid-β-degrading enzyme neprilysin secreted from astrocytes. Herein, we present an overview of irisin/FNDC5's protective roles and mechanisms against Alzheimer's disease.

Astrocytes are neuromodulator cells. Their complex and dynamic morphology regulates neuronal signaling, synaptic plasticity, and neurogenesis. The impact of aging on astrocyte morphology is still under ongoing debate. Therefore, this study aimed to characterize astrocyte morphology in the hippocampus of older rats. 2-, 18-, and 20-month-old male Wistar rats were submitted to the object recognition test to assess their short- and long-term memories. CA1, CA2, CA3, and the dentate gyrus were collected for immunohistochemistry analysis and glial fibrillary acid protein (GFAP) immunostaining. Our results indicate that 20-month-old rats did not recognize or discriminate the novel object in the long-term memory test. Also, GFAP staining was greater in the oldest group for all analyzed areas. Morphometric and fractal analysis indicated shorter branch lengths and smaller sizes for astrocytes of 20-month-old rats. Overall, our results suggest that 20-month-old rats have long-term memory impairment, increased GFAP staining, and astrocyte dystrophy. These age-related alterations in astrocyte morphology are a resource for future studies exploring the role of astrocytes in age-related cognitive decline and age-related diseases.

Neurodegenerative diseases, a substantial global health challenge affecting millions, underscore the pressing need for novel and effective pharmacotherapeutic drugs to address these disorders. In this concern, a library of novel trifluoromethylated arylidene-hydrazinyl-thiazoles has been synthesized and assessed for their anti-neurodegenerative potential. Multicomponent regioselective chemical transformation has been carried out utilizing thiosemicarbazide, trifluoromethylated 1,3-diketones and heteroaryl aldehydes in the presence of N-bromosuccinimide (NBS) in refluxing ethanol. The regioisomeric structure of the synthesized products was unambiguously characterized by employing heteronuclear 2D NMR spectroscopic studies. All the synthesized derivatives were evaluated for their anti-neurodegenerative properties on rat brain hippocampus-derived Neural Stem Cells (NSCs), examining their impact on survival, proliferation and neuronal differentiation in vitro. Among the tested thiazole derivatives, compounds 4a, 4b, 4c, 4f, 4 g, 4b' and 4i' demonstrated a remarkable increase in the number of neuronal cells as compared to the control group within the NSC culture and also exhibited the ability to promote NSC differentiation towards the neuronal lineage. Additionally, the selected compounds showed protection against amyloid beta (Aβ)-induced neurotoxicity in NSCs culture. Incorporating the trifluoromethyl group into the thiazole scaffold is a pivotal factor in augmenting biopotency, resulting in a marked increase in the count of neuronal cells compared to their non-fluorinated thiazole counterparts.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterised by several factors, such as impaired glutamate neurotransmission affecting crucial functions. Neural stem cells (NSCs) are present in the adult brains of all mammalian species and contribute to the continuous generation of neural cells throughout life. The disruption of glutamate levels during the development of AD could impact NSCs' functionality, influencing their response to the microenvironment. In this work, we isolated adult neural stem cells from both triple transgenic (3xTg)-AD mice and age-matched wild type (WT) mice in order to gather information on any differences between them, particularly concerning the potential mechanisms involved in the internalisation of glutamate and its utilisation for energy production. The 3xTg model offers the ability to recapitulate human pathology with both plaque and tangle hallmarks that are involved in the process of glutamate release. In vitro culture 3xTg NSCs showed a slight morphological difference compared to WT cells and a massive reduction of proliferation and viability. Furthermore, 3xTg NSCs displayed an increase in the expression of glutamate transporters and glutamine synthetase, while glutamate dehydrogenase did not show any reduction, which is typical in AD brains. Data obtained from this basic research study suggest a possible involvement of glutamate in the cellular energy balance, indicating an attempted response of NSCs to the cytotoxic microenvironment in the early stage of AD pathology. This finding is of great interest, as it corroborates the hypothesis that targeting the glutamatergic system could be an extremely promising strategy for new therapeutics in AD.

Obstructive sleep apnea (OSA), is associated with dysfunction in the cardiovascular, metabolic and neurological systems. However, the relationship between OSA and memory impairment, intervention effects, and underlying pathways are not well understood. This review summarizes recent advances in the clinical characterization, treatment strategies, and mechanisms of OSA-induced memory impairments. OSA patients may exhibit significant memory declines, including impairments in working memory from visual and verbal sources. The underlying mechanisms behind OSA-related memory impairment are complex and multifactorial with poorly understood aspects that require further investigation. Neuroinflammation, oxidative stress, neuronal damage, synaptic plasticity, and blood-brain barrier dysfunction, as observed under exposures to intermittent hypoxia and sleep fragmentation are likely contributors to learning and memory dysfunction. Continuous positive airway pressure treatment can provide remarkable relief from memory impairment in OSA patients. Other treatments are emerging but need to be rigorously evaluated for cognitive improvement. Clinically, reliable and objective diagnostic tools are necessary for accurate diagnosis and clinical characterization of cognitive impairments in OSA patients. The complex links between gut-brain axis, epigenetic landscape, genetic susceptibility, and OSA-induced memory impairments suggest new directions for research. Characterization of clinical phenotypic clusters can facilitate advances in precision medicine to predict and treat OSA-related memory deficits.

Adult mammalian brains generate new neurons throughout life in two main niches, the dentate gyrus of the hippocampus and the subventricular zone, starting from neural stem cells (NSCs). Adult hippocampal neurogenesis is crucial for learning and memory and decreases during aging. As defined in mouse models, NSCs, which are prevalently quiescent, develop into proliferating progenitor cells, neuroblasts, and immature and mature neurons. Two visions for NSC self-renewal in the dentate gyrus have been proposed, one postulating persistent self-renewal, with cycles of rest and reactivation even in old age, and the other proposing a short-lived NSC model. Single-cell RNA sequencing and clonal studies, discussed in this review, have shed light on the developmental steps of neurogenic cells and the modality of self-renewal, revealing the presence in the adult dentate gyrus of NSC heterogeneous populations, one long-lived and another rapidly depleted at an early age. Another relevant question is whether adult neurogenesis occurs in humans. A few single-cell RNA-seq studies show that new neurons, with prolonged neuronal maturation, are continuously generated at low frequency from stem/progenitor cells, which results in the accumulation of immature granule cell neurons. This suggests an important role of these cells in human neurogenesis and hence interspecies differences in the neurogenic process dynamics. This review is focused on transcriptomic studies that have faced these and other NSC issues by analyzing developmental trajectories of neural cells and NSCs gene expression profiles in specific experimental settings of hippocampal neurogenesis, and also in mouse models with deletion or overexpression of specific genes to reproduce neural pathologies.

Serotonin (5-HT) is a neurotransmitter that also plays an important role in the regulation of vascular tone and angiogenesis. This review focuses on the involvement of the 5-HT system in pathological processes leading to the development of Alzheimer's disease (AD). There is evidence that damage or dysfunction of the 5-HT system contributes to the development of AD, and different subtypes of 5-HT receptors are a potential target for the treatment of AD. A link has been established between AD, depression, stress, and 5-HT deficiency in the brain. There are new data on the role of circadian rhythms in modulating stress, depression, and the 5-HT system; amyloid β (Aβ) plaque clearance; and AD progression. Circadian disruption inhibits Aβ plaque clearance and modulates AD progression. The properties and functions of 5-HT, its receptors, and serotonergic neurons are presented. Special attention is paid to the central role of 5-HT in brain development, including neurite outgrowth, regulation of somatic morphology, motility, synaptogenesis, control of dendritic spine shape and density, neuronal plasticity determining its role in network regeneration, and changes in innervation after brain damage. The results of different studies indicate that the interaction of amyloid β oligomers (AβO) with mitochondria is a sufficient trigger for AD-related neurodegeneration. The action of 5-HT leads to an improvement in mitochondrial quality and the restoration of brain areas after traumatic brain injury, chronic stress, or developmental disorders in AD. The role of a healthy lifestyle and drugs acting on serotonin receptors in the prevention and treatment of AD is discussed.

As life expectancy continues to increase, it becomes increasingly important to extend healthspan by targeting mechanisms associated with aging. Cellular senescence is recognized as a significant contributor to aging and neurodegenerative disorders. This review examines the emerging role of nutraceuticals and functional foods as potential modulators of cellular senescence, which may, in turn, influence the development of neurodegenerative diseases. An analysis of experimental studies indicates that bioactive compounds, including polyphenols, vitamins, and spices, possess substantial antioxidants, anti-inflammatory and epigenetic properties. These nutritional senotherapeutic agents effectively scavenge reactive oxygen species, modulate gene expression, and decrease the secretion of senescence-associated secretory phenotype factors, minimizing cellular damage. Nutraceuticals can enhance mitochondrial function, reduce oxidative stress, and regulate inflammation, key factors in aging and diseases like Alzheimer's and Parkinson's. Furthermore, studies reveal that specific bioactive compounds can reduce senescence markers in cellular models, while others exhibit senostatic and senolytic properties, both directly and indirectly. Diets enriched with these nutraceuticals, such as the Mediterranean diet, have been correlated with improved brain health and the deceleration of aging. Despite these promising outcomes, direct evidence linking these compounds to reducing senescent cell numbers remains limited, highlighting the necessity for further inquiry. This review presents compelling arguments for the potential of nutraceuticals and functional foods to promote longevity and counteract neurodegeneration by exploring their molecular mechanisms. The emerging relationship between dietary bioactive compounds and cellular senescence sets the stage for future research to develop effective preventive and therapeutic strategies for age-related diseases.

Amyloid deposits initiate neuroinflammation by activating astrocytes and microglia in the hippocampus, increasing neuronal vulnerability and loss. Astrocytes, while essential for cerebral function, can contribute to neuronal dysfunction by retracting neuronal synapses, that forms a consequence of neuroinflammation, leading to cognitive deficits in Alzheimer's disease (AD). Upon Amyloid-β (Aβ) deposition, astrocytes become reactive as part of a repair mechanism, however this process can impair neurogenesis resulting in AD progression.

The current study hypothesizes that resveratrol (RSV) can address inflammation and promote neural regeneration, mitigating cognitive decline. Our previous research highlights RSV's homeostatic effect through SIRT1 normalization, which is crucial in preventing AD progression. However, its neurogenic potential in AD remains underexplored.

In this study, Aβ25-35-induced AD rat model was used to study the anti-inflammatory, neurogenic and cellular homeostatic effect of RSV (30 mg/kg) for four weeks.

Results showed increased Doublecortin expressing cells, indicating favorable neurogenesis in hippocampus. Immunofluorescence of microglia and astrocytes in the hippocampus revealed that RSV counteracted their activation by reducing the formation of engulfing microglia and elongated astrocytes. Behavioral assessments using the Morris water maze and cued radial arm maze demonstrated significant improvements in spatial and learning memory. These cognitive improvements were supported by increased choline acetyltransferase and SIRT1 levels.

These findings suggest that RSV effectively reduces neuroinflammation, promotes neurogenesis in the sub granular zone of the hippocampus, and improves learning and memory in both control and AD conditions via SIRT1. This study highlights RSV's potential as a suitable therapeutic agent for AD.

Cerebrovascular reactivity (CVR) shows promise as a biomarker of vascular integrity and may benefit from a repeatable, reliable, and microvasculature-sensitive acquisition. A combined spin- and gradient-echo (SAGE) functional MRI (fMRI) acquisition may improve repeatability and reliability compared to single spin- (SE) and gradient-echo (GRE) fMRI and provide a microvascular-weighted analysis. The most repeatable and reliable MRI acquisition CVR maps were compared across three CVR paradigms: a breath-hold task, a breath modulation task, and a resting state acquisition. SAGE-fMRI data was acquired in fifteen young adults at two timepoints. Mean gray matter (GM) within-subject coefficient of variation (wCV) and intraclass correlation coefficient (ICC) were compared within the quantitative and weighted SAGE-fMRI CVR maps and single GRE- and SE-fMRI CVR. Total and microvascular MRI inputs with lowest wCV and highest ICC were used to compare three CVR paradigms. Total and microvascular weighted SAGE-fMRI CVR had the lowest wCV and highest ICC across paradigms. The breath-hold paradigm produced significantly higher GM CVR estimates. SAGE repeatably and reliably measures CVR and offers a simultaneous, complementary analysis on total and microvascular scales. The breath-hold paradigm showed significantly higher CVR estimates, but less compliance-dependent protocols may be ideal for applications in patient populations.

Neurogenesis is a biological process in which new neurons are generated from neural stem cells (NSCs) in specific neural niches in the brain. Impaired neurogenesis, characterized by the progressive loss of neurons, leads to cognitive and motor disabilities and is a hallmark of central nervous system (CNS) diseases. Conversely, enhancing neurogenesis has been shown to alleviate the symptoms of CNS diseases. Apolipoprotein E (APOE) is a protein that plays various biological roles in CNS diseases. Emerging research indicates that APOE is involved in adult neurogenesis, which is crucial for maintaining the neural progenitor pool in the dentate gyrus (DG) and synaptic activity. Therefore, APOE could be a therapeutic target for promoting neurogenesis in the treatment and intervention of CNS diseases. In this context, we present a comprehensive overview of the clinical evidence supporting the role of APOE in CNS diseases on the basis of a meta-analysis. We also discuss the neurogenic potential of APOE, which has significant implications not only for understanding the biological underpinnings of neurological diseases but also for developing novel treatment strategies for CNS diseases.

Background/Objectives: Dementia involves progressive cognitive and functional deterioration that leads to dependence and overload on family caregivers. This overload has a negative impact on the physical, mental, emotional, and occupational health of caregivers, leading to occupational imbalance and problems arising from an inadequate distribution of time devoted to caregiving. This project aims to evaluate the effects of the technology-based CAREFIT programme, structured around physical activity interventions, education, and psychoemotional and social support, on the health-related quality of life and emotional well-being of informal caregivers. Methods: The experimental group will develop the intervention programme, which will last 8 weeks and combine educational activities, physical activities, and psychoemotional and social support. Before beginning the intervention, the entire experimental group will receive a training session and educational materials on how to access and use the platform. The CAREFIT platform will consist of two educational sessions and two weekly physical sessions, combined with psychoemotional and social support activities that participants must complete. Initial, final, and follow-up evaluations will be conducted. The HRQoL and psychoemotional health (stress, anxiety, depression, and perceived social support and burden) of caregivers of people with dementia will be the main outcome measures. The effects of the intervention on the study variables will be assessed using a repeated-measures analysis of variance (ANOVA). Conclusions: The proposed protocol for the CAREFIT programme represents an innovative and multidisciplinary initiative that leverages a digital platform to promote the well-being of informal caregivers of people with dementia. This approach combines health literacy and strengthened psychoemotional and social support. Through this integration, the goal is to reduce the levels of burden, stress, anxiety, and depression among primary caregivers, while strengthening their self-care capabilities and social support networks.

Alzheimer's disease (AD) and atherosclerosis (AS) are two interacting diseases mostly affecting aged adults. AD is characterized by the deposition of neuritic plaques mainly consisting of Aβ, and AS is defined by the formation of atheromatous plaque along the vascular wall. The shared mechanisms underlying the pathogenesis of AD and AS remain unclear. Here we applied several bioinformatic analyses of bulk sequencing data sets of AD brain tissues and atherosclerotic plaques to seek relevant genes between AD and AS. WIPF3, was identified as the most affected gene in both diseases using weighted gene co-expression network analysis, machine-learning-based Lasso Cox regression analysis and random forest analysis. Furthermore, immune cell infiltration analysis of AS data sets and cell portion of single-cell RNA sequencing data from AD patients revealed an essential role of inflammation in the co-occurrence of AD and AS. Taken together, WIPF3 deficiency and inflammation may simultaneously mediate both AD and AS and could be potential targets for the prevention and therapy of these two closely related diseases.

This study aims to construct an individualized glucose metabolism network using total-body 18F-FDG PET imaging, which provides a comprehensive view of glucose metabolism across various organs, to explore the role of inter-organ interactions in Diabetes Mellitus (DM).

In this study, we constructed covariance metabolic networks using static total-body PET images, normalized by lean body mass, from 36 patients with DM (DM group) and 36 age- and sex-matched healthy controls (HC group). Differences in network properties between the DM and HC groups were evaluated at both group and individual levels. In addition, correlation analysis was performed to explore the relationship between network properties and baseline clinical data in the DM subjects.

We observed that the same edges in the first three edges with the largest values were brain-subcutaneous adipose tissue (SAT) and brain-visceral adipose tissue (VAT) at both group and individual levels. There was a positive correlation between the brain-VAT and BMI and there was a negative correlation between the brain-SAT and age. The most perturbed organ was the brain at both group and individual levels, and there was a positive correlation between the strength of abnormality of brain and age.

This study successfully used static total-body PET imaging to construct individualized glucose metabolism networks for patients with DM, identifying the brain-VAT and brain-SAT as the most significantly altered edge and the brain as the most affected organ. These findings provide novel insights into the role of the brain-white adipose tissue axis in glucose metabolism in DM.