Lycium Barbarum Polysaccharides Improves Cognitive Functions in ICV-STZ-Induced Alzheimer's Disease Mice Model by Improving the Synaptic Structural Plasticity and Regulating IRS1/PI3K/AKT Signaling Pathway.

Lycium barbarum polysaccharide (LBP) have a certain curative effect on hypoglycemic and neuroprotective effects, but the specific mechanism is unclear and needs to be further explored. This study aimed to clarify the mechanisms of LBP in the treatment of ICV-STZ mice model of AD from the perspectives of insulin resistance, IRS1/PI3K/AKT signaling pathway, and synaptic protein expression. We used male C57BL/6J mice injected with STZ (3 mg/kg) in the lateral ventricle as an AD model. After treatment with LBP, the learning and memory abilities of ICV-STZ mice were enhanced, and the pathological changes in brain tissue were alleviated. LBP can regulate the expression of proteins related to the IRS1/PI3K/AKT signaling pathway and thereby reducing Aß deposition and tau protein phosphorylation in the brain of ICV-STZ mice. In addition, LBP also can up-regulate the expression of synaptic proteins. The results indicated that LBP played a neuroprotective role by regulating the IRS1/PI3K/AKT pathway, inhibiting tau protein hyperphosphorylation and improving the expression levels of synapse-related proteins.

Biochemical and Biophysical Characterization of Tau and α-Linolenic Acid Vesicles In Vitro.

Alzheimer's disease (AD) is characterized by the abnormal accumulation of disordered protein, that is, extracellular senile plaques of amyloid-ß (Aß) and intracellular neurofibrillary tangles of Tau. Tau protein has gained the attention in recent years owing to the ability to propagate in a "prion-like" nature. The disordered protein Tau possesses a high positive charge, which allows its binding to anionic proteins and factors. The native disorder of proteins attends the ß-sheet structure from its random-coiled conformation upon charge compensation by various polyanionic agents such as heparin, RNA, etc. Anionic lipids such as arachidonic acid (AA) and oleic acid (OA) are also one of the factors which can induce aggregation of Tau in physiological conditions. The free units of Tau protein can bind to lipid membranes through its repeat domain (RD), the anionic side chains of the membrane lipids induce aggregation of Tau by reducing the activation barrier. In this study, we investigated the role of α-linolenic acid (ALA) as an inducing agent for Tau aggregation in vitro conditions. Omega-3 fatty acids bear a capacity to reduce the pathology of Tau by downregulating the Tau phosphorylation pathway. We have studied by using various biochemical or biophysical methods the potency of ALA as an aggregating agent for Tau. We have implemented different techniques such as SDS-PAGE, transmission electron microscopy, CD spectroscopy to evaluated higher-order aggregates of Tau upon induction by ALA.

α-Linolenic Acid Induces Microglial Activation and Extracellular Tau Internalization.

Neuroinflammation is the brain condition that occurs due to the hyper-activation of brain's immune cells and microglia, over the stimulation of extracellular aggregated proteins such as amyloid plaques and by extracellular Tau as well. The phenotypic changes of microglia from inflammatory to anti-inflammatory can be triggered by many factors, which also includes dietary fatty acids. The classes of omega-3 fatty acids are the majorly responsible in maintaining the anti-inflammatory phenotype of microglia. The enhanced phagocytic ability of microglia might induce the clearance of extracellular aggregated proteins, such as amyloid beta and Tau. In this study, we emphasized on the effect of α-linolenic acid (ALA) on the activation of microglia and internalization of the extracellular Tau seed in microglia.

Dendrobium officinale phenolic extract maintains proteostasis by regulating autophagy in a Caenorhabditis elegans model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease, and accumulating evidence suggested that proteostatic imbalance is a key feature of the disease. Traditional Chinese medicine exhibits a multi-target therapeutic effect, making it highly suitable for addressing protein homeostasis imbalance in AD. Dendrobium officinale is a traditional Chinese herbs commonly used as tonic agent in China. In this study, we investigated protection effects of D. officinale phenolic extract (SH-F) and examined its underlying mechanisms by using transgenic Caenorhabditis elegans models. We found that treatment with SH-F (50 µg/mL) alleviated Aß and tau protein toxicity in worms, and also reduced aggregation of polyglutamine proteins to help maintain proteostasis. RNA sequencing results showed that SH-F treatment significantly affected the proteolytic process and autophagy-lysosomal pathway. Furthermore, we confirmed that SH-F showing maintainance of proteostasis was dependent on bec-1 by qRT-PCR analysis and RNAi methods. Finally, we identified active components of SH-F by LC-MS method, and found the five major compounds including koaburaside, tyramine dihydroferulate, N-p-trans-coumaroyltyramine, naringenin and isolariciresinol are the main bioactive components responsible for the anti-AD activity of SH-F. Our findings provide new insights to develop a treatment strategy for AD by targeting proteostasis, and SH-F could be an alternative drug for the treatment of AD.

Internalization and Endosomal Trafficking of Extracellular Tau in Microglia Improved by α-Linolenic Acid.

Alzheimer's disease (AD) is distinguished by extracellular accumulation of amyloid-beta plaques and intracellular neurofibrillary tangles of Tau. Pathogenic Tau species are also known to display "prion-like propagation," which explains their presence in extracellular spaces as well. Glial population, especially microglia, tend to proclaim neuroinflammatory condition, disrupted signaling mechanisms, and cytoskeleton deregulation in AD. Omega-3 fatty acids play a neuroprotective role in the brain, which can trigger the anti-inflammatory pathways as well as actin dynamics in the cells. Improvement of cytoskeletal assembly mechanism by omega-3 fatty acids would regulate the other signaling cascades in the cells, leading to refining clearance of extracellular protein burden in AD. In this study, we focused on analyzing the ability of α-linolenic acid (ALA) as a regulator of actin dynamics to balance the signaling pathways in microglia, including endocytosis of extracellular Tau burden in AD.

Korean red ginseng polysaccharide as a potential therapeutic agent targeting tau pathology in Alzheimer's disease.

Tau is a microtubule-associated protein that plays a critical role in the stabilization and modulation of neuronal axons. Tau pathology is stronger associated with cognitive decline in patients with Alzheimer's disease (AD) than amyloid beta (Aß) pathology. Hence, tau targeting is a promising approach for the treatment of AD. Previous studies have demonstrated that the non-saponin fraction with rich polysaccharide (NFP) from Korean red ginseng (KRG) can modulate tau aggregation and exert a therapeutic effect on AD. Therefore, we investigated the efficacy of NFP isolated from KRG on tau pathology in experimental models of AD. Our results showed that NFP from KRG ameliorated deposition and hyperphosphorylation of tau in the brain of 3xTg mice. Moreover, NFP from KRG modulated the aggregation and dissociation of tau K18 in vitro. We demonstrated the alleviatory effects of NFP from KRG on hyperphosphorylated tau and tau kinase in okadaic acid-treated HT22 cells. Furthermore, NFP from KRG mitigated Aß deposition, neurodegeneration, and neuroinflammation in 3xTg mice. We revealed the neuroprotective effects of NFP from KRG on tau-induced neuronal loss in HT22 cells. Our results indicate that NFP extracted from KRG is a novel therapeutic agent for the treatment of AD associated with tau pathology.

Exploring the significance of caspase-cleaved tau in tauopathies and as a complementary pathology to phospho-tau in Alzheimer's disease: implications for biomarker development and therapeutic targeting.

Tauopathies are neurodegenerative diseases that typically require postmortem examination for a definitive diagnosis. Detecting neurotoxic tau fragments in cerebrospinal fluid (CSF) and serum provides an opportunity for in vivo diagnosis and disease monitoring. Current assays primarily focus on total tau or phospho-tau, overlooking other post-translational modifications (PTMs). Caspase-cleaved tau is a significant component of AD neuropathological lesions, and experimental studies confirm the high neurotoxicity of these tau species. Recent evidence indicates that certain caspase-cleaved tau species, such as D13 and D402, are abundant in AD brain neurons and only show a modest degree of co-occurrence with phospho-tau, meaning caspase-truncated tau pathology is partially distinct and complementary to phospho-tau pathology. Furthermore, these caspase-cleaved tau species are nearly absent in 4-repeat tauopathies. In this review, we will discuss the significance of caspase-cleaved tau in the development of tauopathies, specifically emphasizing its role in AD. In addition, we will explore the potential of caspase-cleaved tau as a biomarker and the advantages for drug development targeting caspase-6. Developing specific and sensitive assays for caspase-cleaved tau in biofluids holds promise for improving the diagnosis and monitoring of tauopathies, providing valuable insights into disease progression and treatment efficacy.

Tau Phosphorylation Patterns in the Rat Cerebral Cortex After Traumatic Brain Injury and Sodium Selenate Effects: An Epibios4rx Project 2 Study.

Sodium selenate (SS) activates protein phosphatase 2 (PP2A) and reduces phosphorylated tau (pTAU) and late post-traumatic seizures after lateral fluid percussion injury (LFPI). In EpiBioS4Rx Project 2, a multi-center international study for post-traumatic targets, biomarkers, and treatments, we tested the target relevance and modification by SS of pTAU forms and PP2A and in the LFPI model, at two sites: Einstein and Melbourne. In Experiment 1, adult male rats were assigned to LFPI and sham (both sites) and naïve controls (Einstein). Motor function was monitored by neuroscores. Brains were studied with immunohistochemistry (IHC), Western blots (WBs), or PP2A activity assay, from 2 days to 8 weeks post-operatively. In Experiment 2, LFPI rats received SS for 7 days (SS0.33: 0.33 mg/kg/day; SS1: 1 mg/kg/day, subcutaneously) or vehicle (Veh) post-LFPI and pTAU, PR55 expression, or PP2A activity were studied at 2 days and 1 week (on treatment), or 2 weeks (1 week off treatment). Plasma selenium and SS levels were measured. In Experiment 1 IHC, LFPI rats had higher cortical pTAU-Ser202/Thr205-immunoreactivity (AT8-ir) and pTAU-Ser199/202-ir at 2 days, and pTAU-Thr231-ir (AT180-ir) at 2 days, 2 weeks, and 8 weeks, ipsilaterally to LFPI, than controls. LFPI-2d rats also had higher AT8/total-TAU5-ir in cortical extracts ipsilateral to the lesion (WB). PP2A (PR55-ir) showed time- and region-dependent changes in IHC, but not in WB. PP2A activity was lower in LFPI-1wk than in sham rats. In Experiment 2, SS did not affect neuroscores or cellular AT8-ir, AT180-ir, or PR55-ir in IHC. In WB, total cortical AT8/total-TAU-ir was lower in SS0.33 and SS1 LFPI rats than in Veh rats (2 days, 1 week); total cortical PR55-ir (WB) and PP2A activity were higher in SS1 than Veh rats (2 days). SS dose dependently increased plasma selenium and SS levels. Concordant across-sites data confirm time and pTAU form-specific cortical increases ipsilateral to LFPI. The discordant SS effects may either suggest SS-induced reduction in the numbers of cells with increased pTAU-ir, need for longer treatment, or the involvement of other mechanisms of action.

Acteoside ameliorates learning and memory impairment in APP/PS1 transgenic mice by increasing Aß degradation and inhibiting tau hyperphosphorylation.

Alzheimer's disease (AD) is a neurodegenerative disease. Senile plaques and intracellular neurofibrillary tangles are pathological hallmarks of AD. Recent studies have described the improved cognitive and neuroprotective functions of acteoside (AS). This study aimed to investigate whether the improved cognition of AS was mediated by Aß degradation and tau phosphorylation in APP/PS1 mice. The open field, Y maze, and novel object recognition tests were used to assess cognitive behavioral changes. We evaluated the levels of Aß40 and Aß42 in serum, cortex, and hippocampus, and Aß-related scavenging enzymes, phosphorylated GSK3ß and hyperphosphorylated tau in the cortex and hippocampus of APP/PS1 mice by western blotting. Our results revealed that AS treatment ameliorated anxious behaviors, spatial learning, and memory impairment in APP/PS1 mice and significantly reduced Aß deposition in their serum, cortex, and hippocampus. AS significantly increased Aß degradation, inhibited the hyperphosphorylation of tau, and significantly decreased the activity of GSK3ß, which is involved in tau phosphorylation. Altogether, these findings indicated that the beneficial effects of AS on AD-associated anxious behaviors and cognitive impairments could be attributed to promoting Aß degradation and inhibiting tau hyperphosphorylation, which might be partly mediated by GSK3ß.

Dendrobium nobile Lindl. alkaloid decreases Tau hyperphosphorylation via regulating PI3K/Akt/GSK-3ß pathway in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANT: Dendrobium is a traditional and precious Chinese medicinal herb. The Compendium of Materia Medica describes its effects as "benefiting intelligence and dispelling shock, lightning the body and extending life". Dendrobium nobile Lindl. is a precious variety of Dendrobium. Our previous data showed Dendrobium nobile Lindl. alkaloid (DNLA) has significant neuroprotective effects and can improve cognitive dysfunction. However, the specific effects and mechanisms of action of its main active component, DNLA, on cognitive dysfunction caused by Tau hyperphosphorylation, are still unclear. AIM OF THE RESEARCH: This study aimed to determine the effects of DNLA on phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3ß (GSK-3ß) pathway, thus to explore the mechanisms of DNLA to inhibit Tau hyperphosphorylation. MATERIALS AND METHODS: We used wortmannin (WM) and GF-109203X (GFX)-induced hyperphosphorylation of Tau in N2a cells and rats to detect the protective mechanism of DNLA in vivo and in vitro. In vitro, the effect of modeling method on Tau hyperphosphorylation was screened and verified by Western Blotting (WB), and the regulation of Tau hyperphosphorylation and PI3K/Akt/GSK-3ß pathway by different concentrations of DNLA was detected by WB. In vivo, MWM was used to detect the effect of DNLA on model rats, and then Nissl staining was used to detect the loss of neurons. Finally, WB was used to detect the regulation of Tau hyperphosphorylation and PI3K/Akt/GSK-3ß pathway by different concentrations of DNLA. RESULTS: DNLA could rescue the abnormal PI3K/Akt/GSK-3ß pathway and reverse the hyperphosphorylation of Tau induced by WM and GFX in N2a cells. Furthermore, DNLA improved the learning and memory of WM and GFX-induced model rats. Moreover, DNLA regulated PI3K/Akt/GSK-3ß pathway and reduced the p-Tau and neuronal damage in the hippocampus of model rats. CONCLUSION: DNLA may be a promising candidate for reducing hyperphosphorylation of Tau.

Neuroprotection and Mechanism of Gas-miR36-5p from Gastrodia elata in an Alzheimer's Disease Model by Regulating Glycogen Synthase Kinase-3ß.

Alzheimer's disease (AD) is currently the most common neurodegenerative disease. Glycogen synthase kinase 3ß (GSK-3ß) is a pivotal factor in AD pathogenesis. Recent research has demonstrated that plant miRNAs exert cross-kingdom regulation on the target genes in animals. Gastrodia elata (G. elata) is a valuable traditional Chinese medicine that has significant pharmacological activity against diseases of the central nervous system (CNS). Our previous studies have indicated that G. elata-specific miRNA plays a cross-kingdom regulatory role for the NF-κB signaling pathway in mice. In this study, further bioinformatics analysis suggested that Gas-miR36-5p targets GSK-3ß. Through western blot, RT-qPCR, and assessments of T-AOC, SOD, and MDA levels, Gas-miR36-5p demonstrated its neuroprotective effects in an AD cell model. Furthermore, Gas-miR36-5p was detected in the murine brain tissues. The results of the Morris water maze test and western blot analysis provided positive evidence for reversing the learning deficits and hyperphosphorylation of Tau in AD mice, elucidating significant neuroprotective effects in an AD model following G. elata RNA administration. Our research emphasizes Gas-miR36-5p as a novel G. elata-specific miRNA with neuroprotective properties in Alzheimer's disease by targeting GSK-3ß. Consequently, our findings provide valuable insights into the cross-kingdom regulatory mechanisms underlying G. elata-specific miRNA, presenting a novel perspective for the treatment of Alzheimer's disease.

The Role of Traditional Chinese Medicine Natural Products in ß-Amyloid Deposition and Tau Protein Hyperphosphorylation in Alzheimer's Disease.

Alzheimer's disease is a prevalent form of dementia among elderly individuals and is characterized by irreversible neurodegeneration. Despite extensive research, the exact causes of this complex disease remain unclear. Currently available drugs for Alzheimer's disease treatment are limited in their effectiveness, often targeting a single aspect of the disease and causing significant adverse effects. Moreover, these medications are expensive, placing a heavy burden on patients' families and society as a whole. Natural compounds and extracts offer several advantages, including the ability to target multiple pathways and exhibit high efficiency with minimal toxicity. These attributes make them promising candidates for the prevention and treatment of Alzheimer's disease. In this paper, we provide a summary of the common natural products used in Chinese medicine for different pathogeneses of AD. Our aim is to offer new insights and ideas for the further development of natural products in Chinese medicine and the treatment of AD.

Different ratios of Schisandra chinensis and Evodia rutaecarpa combination for treating Alzheimer's disease.

Schisandra chinensis and Evodia rutaecarpa are traditional Chinese herbs that have been used for many years to treat neurodegenerative diseases. In Chinese medicine, multiple herbs are often used in combination to enhance their efficacy, and different combination ratios can produce different therapeutic effects, thus flexibly responding to the needs of various patients. This study aimed to investigate the effects of different ratios of Schisandra and Evodia herbs on learning and memory impairment in rats with Alzheimer's disease (AD) and their specific mechanisms of action. Morris water maze and hematoxylin and eosin (HE) staining experiments were performed to evaluate the effects of different ratios of Schisandra-Evodia on learning memory in AD model rats. Immunohistochemical experiments were performed to investigate the effects of Schisandra-Evodia on the Aß1-42 and P-Tau proteins, and protein immunoblotting (WB) was performed to determine the expression of key proteins in two pathways, BDNF/TrkB/CREB and GSK-3ß/Tau. Our experimental results show that all Schisandra-Evodia groups showed significant neuroprotective effects, improved learning memory impairment, and reduced levels of Aß1-42 and P-Tau proteins in AD model rats. Schisandra-Evodia upregulated BDNF, P-TrkB/TrkB, and P-CREB/CREB protein expression and downregulated GSK-3ß and P-Tau/Tau protein expression. Among the different Schisandra-Evodia ratio groups, the 2:1 group showed the strongest therapeutic effect on AD. Our research results indicate that Schisandra-Evodia can reduce Aß1-42 and P-Tau protein content by modulating the activity of two pathways, BDNF/TrkB/CREB and GSK-3ß/Tau, thus improving neuronal cell damage and cognitive deficits caused by AD. In addition, we found that a Schisandra-Evodia ratio of 2:1 had the most profound therapeutic effect on AD.

Effects of mind-body exercise on cognitive performance in middle-aged and older adults with mild cognitive impairment: A meta-analysis study.

BACKGROUND: To systematically evaluate the clinical efficacy of physical and mental exercise on cognitive performance in middle-aged people with mild cognitive impairment (MCI). METHODS: Computer searches of PubMed, Web of science, Embase, Cochrane Library, China Biomedical Literature Service, Wanfang database, China Knowledge Network, and VIP full-text database of Veep journals were conducted to obtain clinical randomized controlled trials on physical and mental exercise interventions in middle-aged and elderly people with MCI. The literature was screened according to inclusion and exclusion criteria, and the final included literature was subjected to data extraction and risk of bias assessment. Meta-analysis was performed using Review Manager 5.4.1 software, and publication bias test was performed using stata17.0 software. RESULTS: A total of 27 publications with a total of 2565 cases of elderly people with MCI were included. The control group was conventional care, health education, or blank control, and the physical and mental exercise group was exercises including Tai Chi, dance, orthopraxia, and qigong for 30 to 90 minutes each time, 3 to 6 times per week, for a total duration of 8 to 36 weeks. Meta-analysis results showed that Montreal cognitive assessment scores (mean difference [MD] = 2.33, 95% CI [1.55, 3.10], P < .00001), the mini-mental state examination score (MD = 1.73, 95% CI [0.60, 2.86], P = .003), trail making test-A score (MD = -4.00, 95% CI [-6.75, -1.25], P = .004), trail making test-B score (MD = -18.46, 95% CI [-23.87, -13.06], P < .00001), global deterioration scale score (MD = -0.72, 95% CI [-1.09, -0.34], P = .0002), Wechsler Logical Memory Scale score (MD = 2.07, 95% CI [0.03, 4.10], P = .05), berg score (MD = -0.70, 95% CI [0.32, 1.07], P < .0003), cerebrospinal fluid Tau protein level (MD = -166.69, 95% CI [-196.93, -136.45], P < .00001), and cerebrospinal fluid levels of αß1-42 protein (MD = 180.39, 95% CI [134.24, 226.55], P < .00001). CONCLUSION: Mind-body exercise can improve cognitive performance, depressive status, and balance as well as increase αß1-42 protein levels and decrease Tau protein levels in middle-aged and older adults with mild cognitive impairment.

Ginsenoside Rh4 Alleviates Amyloid ß Plaque and Tau Hyperphosphorylation by Regulating Neuroinflammation and the Glycogen Synthase Kinase 3ß Signaling Pathway.

Alzheimer's disease (AD) is a primary neurodegenerative disease. It can be caused by aging and brain trauma and severely affects the abilities of cognition and memory of patients. Therefore, it seriously threatens the mental and physical health of humans worldwide. As a traditional Chinese medicine, ginsenosides have been proven to have a variety of pharmacological activities. Ginsenoside Rh4 (Rh4) is one of the rare ginsenosides with higher pharmacological activity than ordinary ginsenosides, but its effect on alleviating AD and its molecular mechanism have not been studied. Here, we investigated the anti-AD effects of Rh4 and its potential mechanisms using an AD mouse model induced by a combination of AlCl3·6H2O and d-galactose. The results showed that Rh4 could significantly improve the ability of cognizance and reduce neuronal damage in mice. Concurrently, Rh4 attenuates amyloid ß accumulation, increases the density of dendritic spines, and logically inhibits synaptic structural damage as a result of neuronal excessive apoptosis and autophagy. Rh4 can not only inhibit the inflammatory response caused by the overactivation of microglia and astrocytes, reduce the levels of pro-inflammatory factors, increase the level of antioxidant enzymes in serum, and significantly improve the activity of antioxidant enzyme SOD1 in the hippocampus but also inhibit the hyperphosphorylation of tau protein in the hippocampus of mice by regulating the Wnt2b/GSK-3ß/SMAD4 signaling pathway. Together, this study provides a theoretical basis for Rh4 in the treatment of AD and reveals that Rh4 is a potential drug for the treatment of AD.

Effects of de-facing software mri_reface on utility of imaging biomarkers used in Alzheimer's disease research.

Brain imaging research studies increasingly use "de-facing" software to remove or replace facial imagery before public data sharing. Several works have studied the effects of de-facing software on brain imaging biomarkers by directly comparing automated measurements from unmodified vs de-faced images, but most research brain images are used in analyses of correlations with cognitive measurements or clinical statuses, and the effects of de-facing on these types of imaging-to-cognition correlations has not been measured. In this work, we focused on brain imaging measures of amyloid (A), tau (T), neurodegeneration (N), and vascular (V) measures used in Alzheimer's Disease (AD) research. We created a retrospective sample of participants from three age- and sex-matched clinical groups (cognitively unimpaired, mild cognitive impairment, and AD dementia, and we performed region- and voxel-wise analyses of: hippocampal volume (N), white matter hyperintensity volume (V), amyloid PET (A), and tau PET (T) measures, each from multiple software pipelines, on their ability to separate cognitively defined groups and their degrees of correlation with age and Clinical Dementia Rating (CDR)-Sum of Boxes (CDR-SB). We performed each of these analyses twice: once with unmodified images and once with images de-faced with leading de-facing software mri_reface, and we directly compared the findings and their statistical strengths between the original vs. the de-faced images. Analyses with original and with de-faced images had very high agreement. There were no significant differences between any voxel-wise comparisons. Among region-wise comparisons, only three out of 55 correlations were significantly different between original and de-faced images, and these were not significant after correction for multiple comparisons. Overall, the statistical power of the imaging data for AD biomarkers was almost identical between unmodified and de-faced images, and their analyses results were extremely consistent.

Inflammation and the pathological progression of Alzheimer's disease are associated with low circulating choline levels.

Deficiency of dietary choline, an essential nutrient, is observed worldwide, with ~ 90% of Americans being deficient. Previous work highlights a relationship between decreased choline intake and an increased risk for cognitive decline and Alzheimer's disease (AD). The associations between blood circulating choline and the pathological progression in both mild cognitive impairment (MCI) and AD remain unknown. Here, we examined these associations in a cohort of patients with MCI with presence of either sparse or high neuritic plaque density and Braak stage and a second cohort with either moderate AD (moderate to frequent neuritic plaques, Braak stage = IV) or severe AD (frequent neuritic plaques, Braak stage = VI), compared to age-matched controls. Metabolomic analysis was performed on serum from the AD cohort. We then assessed the effects of dietary choline deficiency (Ch-) in 3xTg-AD mice and choline supplementation (Ch+) in APP/PS1 mice, two rodent models of AD. The levels of circulating choline were reduced while pro-inflammatory cytokine TNFα was elevated in serum of both MCI sparse and high pathology cases. Reduced choline and elevated TNFα correlated with higher neuritic plaque density and Braak stage. In AD patients, we found reductions in choline, its derivative acetylcholine (ACh), and elevated TNFα. Choline and ACh levels were negatively correlated with neuritic plaque load, Braak stage, and TNFα, but positively correlated with MMSE, and brain weight. Metabolites L-Valine, 4-Hydroxyphenylpyruvic, Methylmalonic, and Ferulic acids were significantly associated with circuiting choline levels. In 3xTg-AD mice, the Ch- diet increased amyloid-ß levels and tau phosphorylation in cortical tissue, and TNFα in both blood and cortical tissue, paralleling the severe human-AD profile. Conversely, the Ch+ diet increased choline and ACh while reducing amyloid-ß and TNFα levels in brains of APP/PS1 mice. Collectively, low circulating choline is associated with AD-neuropathological progression, illustrating the importance of adequate dietary choline intake to offset disease.

Apitherapy in Post-Ischemic Brain Neurodegeneration of Alzheimer's Disease Proteinopathy: Focus on Honey and Its Flavonoids and Phenolic Acids.

Neurodegeneration of the brain after ischemia is a major cause of severe, long-term disability, dementia, and mortality, which is a global problem. These phenomena are attributed to excitotoxicity, changes in the blood-brain barrier, neuroinflammation, oxidative stress, vasoconstriction, cerebral amyloid angiopathy, amyloid plaques, neurofibrillary tangles, and ultimately neuronal death. In addition, genetic factors such as post-ischemic changes in genetic programming in the expression of amyloid protein precursor, ß-secretase, presenilin-1 and -2, and tau protein play an important role in the irreversible progression of post-ischemic neurodegeneration. Since current treatment is aimed at preventing symptoms such as dementia and disability, the search for causative therapy that would be helpful in preventing and treating post-ischemic neurodegeneration of Alzheimer's disease proteinopathy is ongoing. Numerous studies have shown that the high contents of flavonoids and phenolic acids in honey have antioxidant, anti-inflammatory, anti-apoptotic, anti-amyloid, anti-tau protein, anticholinesterase, serotonergic, and AMPAK activities, influencing signal transmission and neuroprotective effects. Notably, in many preclinical studies, flavonoids and phenolic acids, the main components of honey, were also effective when administered after ischemia, suggesting their possible use in promoting recovery in stroke patients. This review provides new insight into honey's potential to prevent brain ischemia as well as to ameliorate damage in advanced post-ischemic brain neurodegeneration.

Sex differences in metabolic phenotype and hypothalamic inflammation in the 3xTg-AD mouse model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is notably associated with cognitive decline resulting from impaired function of hippocampal and cortical areas; however, several other domains and corresponding brain regions are affected. One such brain region is the hypothalamus, shown to atrophy and develop amyloid and tau pathology in AD patients. The hypothalamus controls several functions necessary for survival, including energy and glucose homeostasis. Changes in appetite and body weight are common in AD, often seen several years prior to the onset of cognitive symptoms. Therefore, altered metabolic processes may serve as a biomarker for AD, as well as a target for treatment, considering they are likely both a result of pathological changes and contributor to disease progression. Previously, we reported sexually dimorphic metabolic disturbances in ~ 7-month-old 3xTg-AD mice, accompanied by differences in systemic and hypothalamic inflammation. METHODS: In the current study, we investigated metabolic outcomes and hypothalamic inflammation in 3xTg-AD males and females at 3, 6, 9, and 12 months of age to determine when these sex differences emerge. RESULTS: In agreement with our previous study, AD males displayed less weight gain and adiposity, as well as reduced blood glucose levels following a glucose challenge, compared to females. These trends were apparent by 6-9 months of age, coinciding with increased expression of inflammatory markers (Iba1, GFAP, TNF-α, and IL-1ß) in the hypothalamus of AD males. CONCLUSIONS: These findings provide additional evidence for sex-dependent effects of AD pathology on energy and glucose homeostasis, which may be linked to hypothalamic inflammation.

Alzheimer's disease (AD), often associated with memory loss, can also affect other parts of the brain and body, resulting in several other symptoms. Changes in appetite and body weight are commonly seen in people with AD, often before they start showing signs of memory loss. These metabolism-related changes are likely due in part to AD affecting a part of the brain called the hypothalamus, which controls important functions like energy balance (calories in vs. calories out) and blood sugar levels. This study aimed to examine whether changes in metabolism and the hypothalamus could serve as early signs of AD, and even help in treating the disease. We also wanted to see if these changes were influenced by biological sex, as two-thirds of AD patients are women, and our previous studies showed many differences between males and females. In this study, we observed male and female mice at different ages to see when these changes began to appear. We found that male AD mice gained less weight, had less body fat, and had better blood sugar control, compared to female AD mice. These differences became noticeable at the same age that we noticed signs of increased inflammation in the hypothalamus of male mice. These findings suggest that AD affects males and females differently, particularly in terms of energy balance and blood sugar control, and this might be related to inflammation in the hypothalamus. This research could provide valuable insights into understanding, diagnosing, and treating Alzheimer's disease.

Methyl donor supplementation reduces phospho-Tau, Fyn and demethylated protein phosphatase 2A levels and mitigates learning and motor deficits in a mouse model of tauopathy.

BACKGROUND: Reduced folate status and elevated levels of circulating homocysteine are modifiable risk factors for cognitive decline and dementia. Disturbances in one-carbon metabolism are associated with the pathological accumulation of phosphorylated tau, a hallmark feature of prevalent dementia, including Alzheimer's disease and subgroups of frontotemporal dementia. METHODS: Here, using transgenic TAU58/2 mouse models of human tauopathy, we tested whether dietary supplementation with L-methylfolate (the active folate form), choline and betaine can reduce tau phosphorylation and associated behavioural phenotypes. RESULTS: TAU58/2 mice fed with the methyl donor-enriched diet showed reduced phosphorylation of tau at the pathological S202 (CP13) and S396/S404 (PHF-1) epitopes and alleviation of associated motor and learning deficits. Compared with mice on the control diet, the decrease in cortical phosphorylated tau levels in mice fed with the methyl donor-enriched diet was associated with enhanced methylation of protein phosphatase 2A, the major brain tau Ser/Thr phosphatase. It also correlated with a reduction in protein levels of Fyn, a tau tyrosine kinase that plays a central role in mediating pathological tau-induced neurodegeneration. Conversely, Fyn expression levels were increased in mice with deficiencies in folate metabolism. CONCLUSIONS: Our findings provide the first experimental evidence that boosting one-carbon metabolism with L-methylfolate, choline and betaine can mitigate key pathological, learning and motor deficits in a tauopathy mouse model. They give support to using a combination of methyl donors as a preventive or disease-modifying strategy for tauopathies.