Background/Objectives: Neurodegenerative diseases like Alzheimer's, Parkinson's, and Amyotrophic lateral sclerosis (ALS) share common molecular pathways, including neuroinflammation and oxidative stress, which complicate the effectiveness of single-target treatments. Garcinia mangostana L. (mangosteen) has shown neuroprotective properties, but previous studies focused on lipophilic xanthones, which have poor bioavailability and uncertain blood-brain barrier permeability. Methods: In the current study, polar metabolites from G. mangostana peel aqueous extract (GMPE) were assessed for potential multi-target interactions via UHPLC-QTOF-MS-based metabolomics, systems pharmacology, and molecular docking analysis. Further, in silico ADMET screening and network-based analyses assessed for overlap between GMPE compounds and genes associated with neurodegeneration (AD, PD, ALS). Results: Analysis of genes linked to AD, PD, and ALS revealed 121 common molecular targets influenced by GMPE metabolites. Network and enrichment analyses indicated that the compounds derived from GMPE may be involved in common pathways related to oxidative stress, neuroinflammation, and neuronal survival. Molecular docking analyses suggest that selected metabolites are likely to exhibit moderate binding affinities to their respective protein targets. Conclusions: The results presented in this study provide evidence that GMPE may possess potential multi-target interactions within common neurodegenerative pathways. However, since the data are based on computational and predictive approaches, these results should be considered hypothesis-generating and warrant further experimental validation.

Mitochondria are essential organelles for cellular energy production and the regulation of diverse biological processes, including apoptosis, redox homeostasis, and intracellular signaling. Although mitochondrial reactive oxygen species (mtROS) act as critical mediators of these functions, the molecular mechanisms underlying mtROS regulation remain poorly understood. This review summarizes current insights into the role of heat shock protein 47 (HSP47) in mitochondrial oxidative stress and mtROS-mediated cellular responses. In addition to its classical function as an endoplasmic reticulum (ER) chaperone, HSP47 translocates to the mitochondria under oxidative stress conditions. This mitochondrial localization promotes mtROS production, thereby triggering apoptotic pathways and redox-sensitive signal transduction. Furthermore, we examine the mechanistic insights linking HSP47 to mitochondrial function and oxidative stress, highlighting their implications for cellular homeostasis and disease pathogenesis. Overall, these findings establish HSP47 as a novel regulator of mtROS generation, suggesting that the HSP47–mtROS axis represents a promising therapeutic target for oxidative stress-related disorders and a potential role for exploring virus-induced cellular responses in future research.

INTRODUCTION:Evidence points to dysregulated Ca2+ in neurons and astrocytes in models of amyloidosis. While most of these data were obtained in vitro or in vivo under anesthesia, less work has investigated these variables in awake ambulating mice. METHODS:Astrocytic Ca2+ fluctuations (GCaMP8f) were imaged concomitantly with vasoreactivity in S1 on a two-photon microscope during rest and ambulation. Single-cell resolution variables were extracted using continuous wavelet transform and traditional ΔF/F measures. RESULTS:Along with increases in amyloid beta (Aβ) accumulation, we found significant reductions in measures of astrocyte functional connectivity, pairwise correlations, and network synchronicity in older 5×FAD mice, with greater decreases in females. Results align with altered gait and reduced astrovascular coupling. DISCUSSION:The results provided here are novel and demonstrate that age and sex are major risk factors for AD; however, central astrovascular dysregulations appear to exist in response to reduced, rather than elevated astrocyte Ca2+ transients. HIGHLIGHTS:Gait analyses reveal older 5×FAD animals display shorter stride length while ambulating. While resting astrocytic calcium activity is increased with age, sex, and genotypes, these results do not explain changes in astrovascular coupling. Only small changes in astrocyte calcium transients and vessel morphology are seen, while the astrocyte-to-vessel correlations (astrovascular coupling) are significantly reduced. Astrocyte network analysis reveals significant reductions in measures of astrocytic communication and activity which are associated with reduced functional vasoreactivity in awake ambulating animals.

While cerebrovascular dysfunction and reactive astrocytosis are extensively characterized hallmarks of Alzheimer's disease (AD) and related dementias, the dynamic relationship between reactive astrocytes and cerebral vessels remains poorly understood. Here, we used jGCaMP8f and two photon microscopy to investigate Ca2+ signaling in multiple astrocyte subcompartments, concurrent with changes in cerebral arteriole activity, in fully awake eight-month-old male and female 5xFAD mice, a model for AD-like pathology, and wild-type (WT) littermates. In the absence of movement, spontaneous Ca2+ transients in barrel cortex occurred more frequently in astrocyte somata, processes, and perivascular regions of 5xFAD mice. However, evoked arteriole dilations (in response to air puff stimulation of contralateral whiskers) and concurrent Ca2+ transients across astrocyte compartments were reduced in 5xFAD mice relative to WTs. Synchronous activity within multi-cell astrocyte networks was also impaired in the 5xFAD group. Using a custom application to assess functional coupling between astrocyte endfeet and immediately adjacent arteriole segments, we detected deficits in Ca2+ response probability in 5xFAD mice. Moreover, endfeet Ca2+ transients following arteriole dilations exhibited a slower onset, reduced amplitude, and lacked relative proportionality to vasomotive activity compared to WTs. The results reveal nuanced alterations in 5xFAD reactive astrocytes highlighted by impaired signaling fidelity between astrocyte endfeet and cerebral arterioles. The results have important implications for the mechanistic underpinnings of brain hypometabolism and the disruption of neurophysiological communication found in AD and other neurodegenerative conditions.

While cerebrovascular dysfunction and reactive astrocytosis are extensively characterized hallmarks of Alzheimer's disease (AD) and related dementias, the dynamic relationship between reactive astrocytes and cerebral vessels remains poorly understood. Here, we used jGCaMP8f and two-photon microscopy to investigate calcium signaling in multiple astrocyte subcompartments, concurrent with changes in cerebral arteriole activity, in fully awake 7-to 8-month-old male and female 5xFAD mice, a model for AD-like pathology, and wild-type (WT) littermates. In the absence of movement, spontaneous calcium transients in barrel cortex occurred more frequently in astrocyte somata, processes, and perivascular regions of 5xFAD mice. However, evoked arteriole dilations (in response to air puff stimulation of contralateral whiskers) and concurrent calcium transients across astrocyte compartments were reduced in 5xFAD mice relative to WTs. Synchronous activity within multicell astrocyte networks was also impaired in the 5xFAD group. Using a custom application to assess functional coupling between astrocyte end feet and immediately adjacent arteriole segments, we detected deficits in calcium response probability in 5xFAD mice. Moreover, end feet calcium transients following arteriole dilations exhibited a slower onset, reduced amplitude, and lacked relative proportionality to vasomotive activity compared with WTs. The results reveal nuanced alterations in 5xFAD reactive astrocytes highlighted by impaired signaling fidelity between astrocyte end feet and cerebral arterioles. The results have important implications for the mechanistic underpinnings of brain hypometabolism and the disruption of neurophysiologic communication found in AD and other neurodegenerative conditions.

Vascular pathology profoundly comorbid with AD pathology could worsen disease progression and reduce treatment efficacy. Knowledge of small vessels and cerebrovascular function in AD mouse models is limited. Investigating vascular related aspects for preclinical AD studies is essential for biomarker development and treatment trials. Therefore, we aim to characterize cerebrovascular amyloid angiopathy (CAA), vascular degeneration, and cerebrovascular function in an aged Tg2576 mouse model of AD. WT and Tg2576 (∼ 2 years of age) were housed in a reversed light cycle room. Cranial window surgery and cranial window installation were performed. After 3 weeks of recovery, the animals were acclimated to an intravital multiphoton imaging platform. To visualize beta-amyloid in the brain, Methoxy-X04 (10mg/kg) was injected the day before the imaging. Cerebrovasculature was visualized by intravascular retro-orbital injection of rhodamine-dextran (5% V/W in saline). This procedure was done while the animals were under anesthesia and securely head-fixed prior to the imaging. Z-stack imaging was performed, and vascular structure was analyzed by using FIJI or ImageJ. Neurovascular coupling was performed to investigate vascular function in awake mice. While imaging penetrating arteriole, air-puff stimulation of contralateral whiskers was conducted and increased vascular diameter is used as an indicator of hyperemic neurovascular function. Investigation of cerebrovascular pathology including CAA, vascular straightness, and vascular blebbing are ongoing. During whisker stimulation, vascular diameter was relatively reduced in Tg2576 compared to WT control mice. Aged Tg2576 exhibits comorbidity of amyloid plaques, cerebral amyloid angiopathy, small vessel pathology and cerebrovascular dysfunction similar to human brain. This aged Tg2576 could be used as a preclinical translational mixed vascular/AD model.

Hyperhomocysteinemia (HHcy)-inducing diets recapitulate cerebral small vessel disease phenotypes in mice including cerebrovascular pathology/dysfunction, neuroinflammation, synaptic deficits, and cognitive decline. We recently showed that astrocyte signaling through calcineurin(CN)/nuclear factor of activated T cells (NFATs) plays a causative role in these phenotypes. Here, we assessed the impact of astrocytic signaling on microglia, which set the inflammatory tone in brain. Seven-to-eight-week-old male and female C57BL/6 J mice received intrahippocampal injections of adeno-associated virus (AAV) expressing EGFP (AAV2/5-Gfa2-EGFP) or AAV expressing the NFAT inhibitor VIVIT (i.e., AAV2/5-Gfa2-VIVIT-EGFP). Mice were then fed with control chow (CT) or B-vitamin-deficient chow for 12 weeks to induce HHcy. Immunohistochemistry and Western blot analyses suggested that expression of the homeostatic microglial marker, P2RY12, responded differently to AAV treatments depending on diet and sex. We next conducted single-cell RNA sequencing (scRNA-seq) to determine if microglial genes and/or clustering patterns were differentially sensitive to diet and AAV, depending on sex. In males, disease-associated microglial genes and subclusters were overrepresented in HHcy-treated mice, while VIVIT promoted the appearance of homeostatic microglial genes and clusters. In contrast, microglial genes in females were less sensitive to diet and AAV treatments, though disease-like patterns were also observed in the HHcy condition. Very few of the HHcy-sensitive microglial genes in females were affected by VIVIT. Though based on small sample sizes, the results suggest a sexually dimorphic influence of astrocyte signaling on microglial transcriptional phenotypes in the context of HHcy and small cerebral vessel disease. However, these interpretations will need to be bolstered with additional biological replicates and more stringent statistical analyses.

BACKGROUND:Cerebral blood perfusion (CBP) plays a vital role in delivering oxygen and essential nutrients to support neuronal activity. Researchers commonly use mouse models with magnetic resonance imaging (MRI) to study CBP and brain function. However, a major challenge in these studies is the use of anesthesia, which significantly alters cerebrovascular dynamics and metabolic activity. NEW METHOD:A 3D-printed, custom-designed frame and head mounting plate were used with an existing Bruker mouse cradle. To evaluate the repeatability of CBP measurements in awake versus anesthetized conditions, we used a flow-sensitive alternating inversion recovery (FAIR) sequence on a wild-type mouse that underwent a three-day training before scanning to acclimate it to the MRI environment. RESULTS:CBP was significantly higher under anesthesia than in the awake condition for both the whole brain and cortex (P < 0.001). Under anesthesia, the mean perfusion for was 70.9 ± 5.6 ml/min/100 g for the whole brain and 67.8 ± 8.5 ml/min/100 g for just the cortex. Under awake conditions, the whole brain perfusion was 51.1 ± 3.3 ml/min/100 g and 46.7 ± 3.4 ml/min/100 g for the cortex. Perfusion variability, measured by variance and standard deviation, was consistently higher under anesthesia. COMPARISON WITH EXISTING METHODS:We built a unique mouse head stabilizing system for MRI and are the first to have specifically focused on CBP during awake conditions. CONCLUSIONS:Our findings confirm that anesthesia significantly increases CBP, affecting the accuracy, reproducibility and relevance of perfusion-related studies. Accordingly, we developed a practical, MRI-compatible setup for imaging awake mice and used it to measure perfusion for more reliable neuroimaging research.

White matter disease, a broad-spectrum term that covers various types of white matter lesions and degeneration, is strongly related to age-related neurodegenerative disorders including Alzheimer's disease (AD), and vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's related dementias (ADRD). There is no specific treatment for white matter disease. Therefore, basic research and clinical studies are essential for future outcomes. Since its formation in 2020, the Albert Research Institute for White Matter and Cognition (ARIWMC) mission has been to support white matter research by providing a forum for communication where basic and clinical scientists meet to discuss and debate new knowledge and guidelines for studying white matter in dementia. The 4th annual ARIWMC workshop was held on May 31-June 2, 2023, where researchers met to set strategies for clinical trial readiness. Significant discussion by participants advocated research on multiple levels, including molecular, cellular, metabolic, behavioral, and risk factors that contribute to disease etiology and regeneration processes. Moreover, participants also addressed identifying and validating biomarkers and functional studies in animal models and human trials that are key steps for treatment development. Other areas that were discussed included epidemiological studies and pragmatic clinical trials where health care researchers and everyday medical practice support risk factor management or healthy lifestyle, and prevention trials could mitigate the incident of the disease. In summary, this workshop fostered a better understanding of how white matter lesions contribute to cognitive impairment from bench-to-biomarker-to-bedside-to-translational approaches which will facilitate and support the discovery and development of therapies and prevention strategies that facilitate a healthy brain and reduce white matter-related pathologies associated with and contributing to VCID and ADRD.

Astrocytes are a glial cell type responsible for many protective functions in the brain. While they are primarily recognized for regulating synaptic activity, they’re also essential for maintaining the neurovascular unit, and cerebral hyperperfusion during metabolic demand. Calcium signaling has been identified as a regulatory process for these functions. Amyloid Beta deposits (Aβ) are a primary diagnostic marker of Alzheimer’s disease, and are linked to synaptic degeneration, astrocyte reactivity, and cognitive decline. Alzheimer’s disease also frequently presents with vascular damage and hypoperfusion, suggesting impaired astrocyte function. We investigated the impact of amyloid burden on stimulation-evoked vasoreactivity and astrocyte calcium signaling to determine potential patterns of physiological impairment that may contribute to Alzheimer’s disease pathology. Six-month-old 5XFAD and littermate control mice were injected with AAV2/5-Gfa104-jGCaMP8f into barrel cortex and imaged three weeks later, while awake, using two-photon microscopy. Neurovascular coupling experiments were conducted using timed air puff stimulation of whiskers, and calcium signals were recorded from activated astrocytes. Calcium transient properties were analyzed over different cellular compartments by custom developed Matlab applications. Vascular tone in response to stimulation was also measured, and correlations calculated with endfeet signaling. Astrocytes from 5XFAD mice showed a significant reduction in calcium signaling amplitudes, (F(1,53) = 8.735, p = 0.0047, n = 25,32) compared to wild type controls with a significant deficit in female 5XFAD mice. Correlations between other signaling properties such as rise/decay kinetics, and network connectivity were also characterized between the 5XFAD and control mice. Astrocyte endfoot compartments also showed reduced transient amplitudes. (F(1,30) = 3.226, p = 0.033, n = 17,15) Neurovascular coupling in the 5XFAD mice was reduced (F(1,39) = 2.511, p = 0.015, n = 20,19) despite no changes in arteriole elasticity. A correlation between astrocyte calcium signaling and the magnitude of stimulation-induced vasodilation was observed in wild-type mice but not in the 5XFAD group. Amyloid induced pathology impairs the brain’s adaptivity to neuronal stimuli at the neurovascular unit. The uncoupling between vasoreactivity and astrocyte signaling processes implies that amyloid accumulation may render the brain vulnerable to conditions of neuronal hyperexcitability and metabolic dysregulation observed in Alzheimer’s disease.

Several forms of cerebrovascular pathology are highly comorbid with clinical hallmarks of Alzheimer's disease. These understudied pathological lesions could accelerate disease progression and affect treatment efficacy. Here, we aim to investigate whether aging and a genetic predisposition to Alzheimer's disease can worsen cerebrovascular architecture and function. Cranial window surgery was performed for intravital two-photon imaging to investigate vascular architecture, pathology, and function in the brains of young (3-5 months) and old (24 months) wild-type and Alzheimer's mouse model (Tg2576). Methoxy-X04 was used to identify Aβ plaques and cerebral amyloid angiopathy (CAA), while rhodamine dextran was used to visualize the bloodstream. Air-puff stimulation of contralateral whiskers was applied to induce penetrating arteriole dilation as a measure of neurovascular coupling in awake mice. Human brain sections were used as reference pathology. Immunochemistry and immunofluorescence were employed to confirm vascular pathology and abnormalities. A reduction in neurovascular function was observed in aged wild-type mice, and more severe impairment was found in vessels with CAA pathology in Tg2576 brains. Beta amyloid predisposition increased cortical leptomeningeal and penetrating vessel aneurysms, both blebbing and saccular. Microvessel tortuosity characteristics, including curved, looped, and folded vessels, were increased in aged wild-type mice and extensively increased in Tg2576 mice. Cerebrovascular integrity, indicated by lectin staining, was reduced, and the astrocyte marker GFAP was increased in Tg2576 compared to wild-type mice. These results highlight that the vascular pathology found in Tg2576 brains recapitulates the vascular pathology found in human brains. These results emphasized the impact of aging and Aβ predisposition on vascular architectural degeneration and dysfunction. These findings provide translational imaging approaches that could be used for further investigation of pathogenesis, pathophysiology and treatment development for AD and vascular-related neurodegenerative diseases.

Atherosclerosis is a persistent inflammatory disorder influenced by oxidative stress and lipid imbalances, and it continues to be a major contributor to cardiovascular diseases. Rich in catechins and flavonoids, green tea pressurized hot water extract (GPHWE) demonstrated potent antioxidant activity through DPPH, ABTS, hydroxyl, and nitric oxide scavenging assays. In vitro, GPHWE protected RAW264.7 macrophages from oxidized LDL (Ox-LDL)-induced cytotoxicity and apoptosis by mitigating oxidative stress and enhancing cell survival. Animal studies using mice fed a high-fat diet (HFD) revealed notable improvements in lipid profiles, including decreases in total cholesterol, LDL, the atherosclerosis index (AI), the coronary risk index (CRI), and triglycerides, as well as lower levels of malondialdehyde (MDA), an indicator of oxidative stress. These results were comparable to those achieved with Simvastatin. Molecular docking studies indicated strong binding affinities of catechins to essential targets such as LOX-1, HMG-CoA reductase, caspase-3, and Nrf2, implying that the mechanisms of GPHWE involve antioxidant properties, regulation of lipids, and stabilization of plaques. The catechins of GPHWE, including epigallocatechin gallate (EGCG), epicatechin gallate (ECG), and epigallocatechin (EGC), were tentatively identified through qualitative analysis performed by UHPLC-QTOF-MS. This comprehensive approach positions GPHWE as a promising natural remedy for preventing atherosclerosis and reducing cardiovascular risk.

Mutations in the human granulin (GRN) gene are associated with multiple diseases, including dementia disorders such as frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). We studied a Grn knockout (Grn-KO) mouse model in order to evaluate a potential therapeutic strategy for these diseases using nicorandil, a commercially available agonist for the ABCC9/Abcc9-encoded regulatory subunit of the "K+ATP" channel that is well-tolerated in humans. Aged (13 months) Grn-KO and wild-type (WT) mice were treated as controls or with nicorandil (15 mg/kg/day) in drinking water for 7 months, then tested for neurobehavioral performance, neuropathology, and gene expression. Mortality was significantly higher for aged Grn-KO mice (particularly females), but there was a conspicuous improvement in survival for both sexes treated with nicorandil. Grn-KO mice performed worse on some cognitive tests than WT mice, but Morris Water Maze performance was improved with nicorandil treatment. Neuropathologically, Grn-KO mice had significantly increased levels of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytosis but not ionized calcium binding adaptor molecule 1 (IBA-1)-immunoreactive microgliosis, indicating cell-specific inflammation in the brain. Expression of several astrocyte-enriched genes, including Gfap, were also elevated in the Grn-KO brain. Nicorandil treatment was associated with a subtle shift in a subset of detected brain transcript levels, mostly related to attenuated inflammatory markers. Nicorandil treatment improved survival outcomes, cognition, and inflammation in aged Grn-KO mice.

Background: Calcineurin (CN) is a Ca2+/calmodulin-dependent protein phosphatase. In healthy tissue, CN exists mainly as a full-length (similar to 60 kDa) highly-regulated protein phosphatase involved in essential cellular functions. However, in diseased or injured tissue, CN is proteolytically converted to a constitutively active fragment that has been causatively-linked to numerous pathophysiologic processes. These calpain-cleaved CN fragments (triangle CN) appear at high levels in human brain at early stages of cognitive decline associated with Alzheimer's disease (AD).New method: We developed a monoclonal antibody to triangle CN, using an immunizing peptide corresponding to the C-terminal end of the triangle CN fragment.Results: We obtained a mouse monoclonal antibody, designated 26A6, that selectively detects triangle CN in Western analysis of calpain-cleaved recombinant human CN. Using this antibody, we screened both pathological and normal human brain sections provided by the University of Kentucky's Alzheimer's Disease Research Center. 26A6 showed low reactivity towards normal brain tissue, but detected astrocytes both surrounding AD amyloid plaques and throughout AD brain tissue. In brain tissue with infarcts, there was considerable concentration of 26A6-positive astrocytes within/around infarcts, suggesting a link with anoxic/ischemia pathways.Comparison with existing method: The results obtained with the new monoclonal are similar to those obtained with a polyclonal we had previously developed. However, the monoclonal is an abundant tool available to the dementia research community.Conclusions: The new monoclonal 26A6 antibody is highly selective for the triangle CN proteolytic fragment and labels a subset of astrocytes, and could be a useful tool for marking insidious brain pathology and identifying novel astrocyte phenotypes.

Historically known as neuronal support cells, astrocytes are now widely studied for their close structural and functional interactions with multiple neural cell types and cerebral vessels where they maintain an ideal environment for optimized brain function. Under pathological conditions, astrocytes become reactive and lose key protective functions. In this commentary, we discuss our recent work in The Journal of Neuroscience (Sompol et al., 2023) that showed Ca2+ dysregulation in reactive astrocytes, as well as hyperactivation of the Ca2+-dependent protein phosphatase calcineurin (CN) and the Nuclear Factor of Activated T Cells (NFATs), in a diet-induced hyperhomocystienemia (HHcy) mouse model of Vascular Contributions to Cognitive Impairment and Dementia (VCID). Intravital multiphoton imaging coupled with whisker stimulation was used to explore astrocyte Ca2+ signaling and neurovascular function under active phase, fully awake conditions. Interestingly, evoked Ca2+ transients in individual astrocytes were greater, even though intercorrelated Ca2+ signaling across networks of astrocytes was impaired in HHcy mice. Blockade of astrocytic CN/NFAT reduced signs of astrocyte reactivity, normalized cerebrovascular function, and improved hippocampal synaptic strength and hippocampal dependent cognition in HHcy mice, revealing a previously unrecognized deficit regarding neuron-astrocyte-vascular interactions. These findings strongly support the use of astrocyte targeting strategies to mitigate pathophysiological changes associated with VCID and other Alzheimer’s-related dementias.

Mitragyna speciosa Korth. Havil (MS) has a traditional use in relieving pain, managing hypertension, treating cough, and diarrhea, and as a morphine substitute in addiction recovery. Its potential in addressing Alzheimer’s disease (AD), a neurodegenerative condition with no effective treatments, is under investigation. This study aims to explore MS mechanisms in treating AD through network pharmacology, molecular docking, and in vitro studies. Using network pharmacology, we identified 19 MS components that may affect 60 AD-related targets. The compound–target network highlighted significant interactions among 60 nodes and 470 edges, with an average node degree of 15.7. The KEGG enrichment analysis revealed Alzheimer’s disease (hsa05010) as a relevant pathway. We connected 20 targets to tau and β-amyloid proteins through gene expression data from the AlzData database. Docking studies demonstrated high binding affinities of MS compounds like acetylursolic acid, beta-sitosterol, isomitraphylline, and speciophylline to AD-related proteins, such as AKT1, GSK3B, NFκB1, and BACE1. In vitro studies showed that ethanolic (EE), distilled water (DWE), and pressurized hot water (PHWE) extracts of MS-treated 100 μM H2O2-induced SH-SY5Y cells significantly reduced oxidative damage. This research underscores the multi-component, multi-target, and multi-pathway effects of MS on AD, providing insights for future research and potential clinical applications.

Many coronavirus disease 2019 (COVID-19) positive individuals exhibit abnormal electroencephalographic (EEG) activity reflecting "brain fog" and mild cognitive impairments even months after the acute phase of infection. Resting-state EEG abnormalities include EEG slowing (reduced alpha rhythm; increased slow waves) and epileptiform activity. An expert panel conducted a systematic review to present compelling evidence that cognitive deficits due to COVID-19 and to Alzheimer's disease and related dementia (ADRD) are driven by overlapping pathologies and neurophysiological abnormalities. EEG abnormalities seen in COVID-19 patients resemble those observed in early stages of neurodegenerative diseases, particularly ADRD. It is proposed that similar EEG abnormalities in Long COVID and ADRD are due to parallel neuroinflammation, astrocyte reactivity, hypoxia, and neurovascular injury. These neurophysiological abnormalities underpinning cognitive decline in COVID-19 can be detected by routine EEG exams. Future research will explore the value of EEG monitoring of COVID-19 patients for predicting long-term outcomes and monitoring efficacy of therapeutic interventions. HIGHLIGHTS: Abnormal intrinsic electrophysiological brain activity, such as slowing of EEG, reduced alpha wave, and epileptiform are characteristic findings in COVID-19 patients. EEG abnormalities have the potential as neural biomarkers to identify neurological complications at the early stage of the disease, to assist clinical assessment, and to assess cognitive decline risk in Long COVID patients. Similar slowing of intrinsic brain activity to that of COVID-19 patients is typically seen in patients with mild cognitive impairments, ADRD. Evidence presented supports the idea that cognitive deficits in Long COVID and ADRD are driven by overlapping neurophysiological abnormalities resulting, at least in part, from neuroinflammatory mechanisms and astrocyte reactivity. Identifying common biological mechanisms in Long COVID-19 and ADRD can highlight critical pathologies underlying brain disorders and cognitive decline. It elucidates research questions regarding cognitive EEG and mild cognitive impairment in Long COVID that have not yet been adequately investigated.

Background Alzheimer’s disease (AD) is one of the multifaceted neurodegenerative diseases influenced by many genetic and epigenetic factors. Genetic factors are merely not responsible for developing AD in the whole population. The studies of genetic variants can provide significant insights into the molecular basis of Alzheimer’s disease. Our research aimed to show how genetic variants interact with environmental influences in different parts of the world. Methodology We searched PubMed and Google Scholar for articles exploring the relationship between genetic variations and global regions such as America, Europe, and Asia. We aimed to identify common genetic variations susceptible to AD and have no significant heterogeneity. To achieve this, we analyzed 35 single-nucleotide polymorphisms (SNPs) from 17 genes (ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, TOMM40, MS4A6A, ARID5B, SORL1, APOC1, MTHFD1L, BDNF, TFAM, and PICALM) from different regions based on previous genomic studies of AD. It has been reported that rs3865444, CD33, is the most common polymorphism in the American and European populations. From TOMM40 and APOE rs2075650, rs429358, and rs6656401, CR1 is the common investigational polymorphism in the Asian population. Conclusion The results of all the research conducted on AD have consistently shown a correlation between genetic variations and the incidence of AD in the populations of each region. This review is expected to be of immense value in future genetic research and precision medicine on AD, as it provides a comprehensive understanding of the genetic factors contributing to the development of this debilitating disease.

Amyloid deposits (Aβ) in the brain are a primary diagnostic marker of Alzheimer’s disease, and are associated with the degeneration of synapses and cognitive decline. However, recent advances in cell specific approaches have revealed that glial processes may also contribute to the progression of disease pathology. Astrocytes are a glial cell in the brain responsible for a plethora of essential functions in the brain, such as the removal of synaptic glutamate, and control over cerebrovascular function. Astrocyte Ca2+ signaling is closely coupled to these functions. These pathways are dysregulated with disease onset, and contribute to astrocyte reactivity. Our group showed previously in a diet model of VCID, that changes in astrocyte calcium signaling and network synchronicity were associated with deficits in cerebrovascular function. Here we examined the spatial and temporal relationship of astrocyte Ca2+ signals to neurovascular coupling in 5XFAD mice to determine the relationship between reactive astrocytes and cerebrovascular function. 5XFAD and littermate controls aged to 6 months were injected with AAV2/5-Gfa104-jGCaMP8f into barrel cortex before cranial window installation. At 7 months, mice were briefly anaesthetized before retroorbital injection of 500kb rhodamine dextran. Mice were then imaged awake under a two-photon microscope for functional hyperemia measures in response to timed air puff whisker stimulation. Spontaneous and evoked Ca2+ transients were measured by ∆F/F calculation of Ca2+ peaks extracted by custom MATLAB algorithms. Analysis of astrocyte endfoot Ca2+ was measured along vessels stimulated for neurovascular coupling to relate vasoactivity to Ca2+ signaling kinetics and intensity. 5XFAD mice showed a significant reduction is astrocyte Ca2+ rise time kinetics compared to wild type controls, as well as parameters of functional hyperemia. Timing of neurovascular coupling in response to stimulation and the latency of astrocyte calcium kinetics was characterized for the 5XFAD model and shown to differ between soma and endfoot processes. Amyloid induced pathology induces changes in astrocyte Ca2+ signaling. Dysregulation of astrocyte signaling may have a mechanistic role in the kinetics of neurovascular coupling and/or cerebrovascular dysfunction with disease progression. However, further analysis of astrocyte endfoot coverage and manipulation of astrocyte signaling during functional hyperemia is needed to further clarify mechanism.