Background Alzheimer Research Articles

An endophenotype network strategy uncovers YangXue QingNao Wan suppresses Aβ deposition, improves mitochondrial dysfunction and glucose metabolism

BackgroundAlzheimer's disease (AD), an escalating global health issue, lacks effective treatments due to its complex pathogenesis. YangXue QingNao Wan (YXQNW) is a China Food and Drug Administration (CFDA)- approved TCM formula that has been repurposed in clinical Phase II for the treatment of AD. Identifying YXQNW's active ingredients and their mechanisms is crucial for developing effective AD treatments. PurposeThis study aims to elucidate the anti-AD effects of YXQNW and to explore its potential therapeutic mechanisms employing an endophenotype network strategy. MethodsHerein we present an endophenotype network strategy that combines active ingredient identification in rat serum, network proximity prediction, metabolomics, and in vivo experimental validation in two animal models. Specially, utilizing UPLC-Q-TOF-MS/MS, active ingredients are identified in YXQNW to build a drug-target network. We applied network proximity to identify potential AD pathological mechanisms of YXQNW via integration of drug-target network, AD endophenotype gene sets, and human protein interactome, and validated related mechanisms in two animal models. In a d-galactose-induced senescent rat model, YXQNW was administered at varying doses for cognitive and neuronal assessments through behavioral tests, Nissl staining, and transmission electron microscopy (TEM). Metabolomic analysis with LC-MS revealed YXQNW's influence on brain metabolites, suggesting therapeutic pathways. Levels of key proteins and biochemicals were measured by WB and ELISA, providing insights into YXQNW's neuroprotective mechanisms. In addition, 5×FAD model mice were used and administered YXQNW by gavage for 14 days at two doses. Amyloid-β levels, transporter expression, and cerebral blood flow have been detected by MRI and biochemical assays. ResultsThe network proximity analysis showed that the effect of YXQNW on AD was highly correlated with amyloid β, synaptic function, glucose metabolism and mitochondrial function. The results of metabolomics combined with in vivo experimental validation suggest that YXQNW has the potential to ameliorate glucose transport abnormalities in the brain by upregulating the expression of GLUT1 and GLUT3, while further enhancing glucose metabolism through increased O-GlcNAcylation and mitigating mitochondrial dysfunction via the AMPK/Sirt1 pathway, thereby improving d-galactose-induced cognitive deficits in rats. Additionally, YXQNW treatment significantly decreased Aβ1–42 levels and enhanced cerebral blood flow (CBF) in the hippocampus of 5×FAD mice. while mechanistic findings indicated that YXQNW treatment increased the expression of ABCB1, an Aβ transporter, in 5×FAD model mice to promote the clearance of Aβ from the brain and alleviate AD-like symptoms. ConclusionsThis study reveals that YXQNW may mitigate AD by inhibiting Aβ deposition and ameliorating mitochondrial dysfunction and glucose metabolism, thus offering a promising therapeutic approach for AD.

A-120 Analytical and Clinical Verification of the Elecsys® Alzheimer’s Disease Cerebrospinal Fluid Biomarkers pTau/Abeta42 and Total-Tau/Abeta42

Abstract Background Alzheimer’s disease (AD) is the most common form of dementia characterized by amyloid beta (Abeta) plaques and neurofibrillary tau tangles in the brain. Cerebrospinal fluid (CSF) biomarkers Abeta42, total tau (tTau), and phosphorylated tau (pTau181) offer a high degree of sensitivity and specificity in the diagnosis of AD and have utility in monitoring disease progression. AD biomarker ratios, pTau181/Abeta42 and tTau/Abeta42, correlate with amyloid positron emission tomography (PET) imaging, and several assays have received FDA clearance. This study was designed to evaluate the analytical performance and clinical utility of AD-related Abeta and tau biomarkers on the Roche cobas e601. Methods Precision studies were performed using Roche PreciControl kits. Intra- and inter-precision samples were tested ten times in a single day or twice a day for ten days, respectively. Five levels of Roche Calcheck material were measured in triplicate for linearity. Method comparison was carried out using 39 samples from the Elecsys CSF Correlation Sample Panel from Roche. Qualitative comparisons to amyloid PET Centiloid scores were performed using 35 CSF samples (n=11 PET negative, n=24 PET positive). CSF samples and PET interpretation were obtained from the Cleveland Clinic Institutional Review Board approved Cleveland Alzheimer's Disease Research Center (CADRC) and Cleveland Clinic Lou Ruvo Center for Brain Health Aging and Neurodegenerative Disease Biobank (LRCBH-Biobank). Results Conclusions Evaluation of AD biomarkers on the Roche cobas e601 revealed reliable precision and analytical accuracy. The pTau181/Abeta42 and tTau/Abeta42 ratios demonstrated excellent positive agreement when compared to amyloid PET, but poor negative agreement. This may be due to the small sample size of PET-negative patients. Alternatively, as amyloid PET detects neuritic plaque accumulation, the CSF biomarker-positive/PET-negative patients may have early non-neuritic amyloid plaque pathology not detectable by imaging. Overall, this assay is suitable for use and may serve as a valuable tool in AD diagnosis.

Genetic variability of incretin receptors affects the occurrence of neurodegenerative diseases and their characteristics

BackgroundAlzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases. Their treatment options are rather limited, and no neuroprotective or disease-modifying treatments are available. Anti-diabetic drugs, such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonists, have been suggested as a potential therapeutic option. AimsAssess GLP1R and GIPR genetic variability in relation to AD- and PD-related phenotypes. MethodsAD, PD patients and healthy control subjects were included in the study. Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease were measured in AD patients, while cognitive impairment was evaluated in PD. All participants were genotyped for three SNPs: GLP1R rs10305420, GLP1R rs6923761 and GIPR rs1800437. ResultsGLP1R rs10305420 genotypes were associated with increased odds for AD and PD development. GLP1R rs10305420 and GLP1R rs6923761 genotypes were significantly associated with Aβ42/40 ratio (p = 0.041 and p = 0.050), while GLP1R rs6923761 was also associated with p-tau levels (p = 0.022). Finally, GIPR rs1800437 heterozygotes as well as carriers of at least one GIPR rs1800437 C allele presented with increased odds for the development of dementia in PD (OR = 1.92; 95 % CI = 1.05–3.51; p = 0.034 and OR = 1.95; 95 % CI = 1.08–3.52; p = 0.027, respectively). ConclusionGLP1R and GIPR genetic variability may affect the occurrence of AD and PD and is also associated with AD CSF biomarkers for Alzheimer's disease and dementia in PD. The data on GLP1R and GIPR genetic variability may support the function of incretin receptors in neurodegeneration.

Early intervention using long-term rhythmic pulsed magnetic stimulation alleviates cognitive decline in a 5xFAD mouse model of Alzheimer's disease

BackgroundAlzheimer's disease (AD) is the most prevalent form of dementia, but no effective therapeutic strategy is available to date. Rhythmic magnetic stimulation is an attractive means of neuron modulation that could be beneficial for restoring learning and memory abilities. ObjectiveTo assess the effect of a compound pulsed rhythmic magnetic field (cPMF) on cognition during AD progression and to explore the appropriate cPMF intervention period. MethodsFemale 5xFAD mice aged 10 weeks and 18 weeks were exposed to cPMF with a carrier frequency of 40 Hz, repeated at 5 Hz for 1 h/d for 8 consecutive weeks. The Morris water maze (MWM) test was used for cognitive behavioral assessment. Furthermore, changes in molecular pathology within the brain were detected using immunofluorescence staining and real-time PCR. Results10-week-old AD mice treated with cPMF explored the target quadrant more frequently than sham-exposed AD mice in MWM test, exhibiting improved learning and memory abilities. Additionally, cPMF exposure alleviated Aβ plaque deposition and astrogliosis in the AD brain. Moreover, neurotrophic factor fibroblast growth factor 1 (FGF1) in the AD brain was upregulated by cPMF treatment. However, in 18-week-old AD mice treated with cPMF, cognitive performance and Fgf1 gene expression were not significantly improved, although Aβ plaque deposition and astrogliosis were alleviated. ConclusionEarly intervention via long-term rhythmic cPMF stimulation may alleviate the histopathological features and enhance neuroprotective gene Fgf1 expression, thereby improving the cognitive performance of 5xFAD mice, which should provide promising insight for the clinical treatment of patients with AD.

Kaixinsan regulates neuronal mitochondrial homeostasis to improve the cognitive function of Alzheimer's disease by activating CaMKKβ-AMPK-PGC-1α signaling axis

BackgroundAlzheimer's disease (AD) is a neurodegenerative disease primarily characterized by cognitive impairments. With the intensification of population aging, AD has become a major health issue faced by the elderly. Kaixinsan, a classical traditional Chinese prescription consists of Panax ginseng C. A. Mey., Polygala tenuifolia Willd., Poria cocos (Schw.) Wolf and Acori Tatarinowii rhizoma, is commonly used in clinical for treating memory decline. However, its mechanism remains unclear, which hinders its popularization and application. MethodMorris water maze (MWM) was performed to evaluate the effect of Kaixinsan on improving learning and memory ability in SAMP8 (senescence-accelerated mouse prone 8, an AD model mice) mice. Nissl staining, TdT-mediated dUTP Nick End Labeling (TUNEL) and western blotting (Bax and Bcl-2) were used to confirm the effect of Kaixinsan on the neuronal structure and apoptosis of SAMP8 mice. ultra performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was performed to identify the distribution components of the brain tissue after receiving Kaixinsan extraction. Based on the identified brain distribution components, the mechanism of Kaixinsan improving the cognitive function was predicted by network pharmacology. Then, using HSP60 as mitochondrial marker and RBFOX3 as neuron marker, immunofluorescence co-localization was used to confirm the effect of Kaixinsan on neuronal mitochondria quantity in SAMP8 mice. Using western blotting to detect the expression of predicted proteins (AMPK, CaMKKβ, PGC-1α and HSP90) affecting mitochondrial homeostasis. To further confirm the mechanism of Kaixinsa. The authors replicated SH-SY5Y cell injury model induced by Amyloid β - protein fragment 25-35 (Aβ25-35) and compared the effects of serum containing Kaixinsan on apoptosis of injured SH-SY5Y cells (detected by flow cytometer) and the expression level of apoptosis-associated protein (Bax and Bcl-2) and mitochondrial homeostasis related proteins (AMPK, CaMKKβ, PGC-1α and HSP90), with or without the addition of CaMKKβ inhibitor (STO-609). ResultsThe results indicate that Kaixinsan can improve the cognitive function of SAMP8 mice, alleviate the hippocampal tissue lesions and inhibit neuron apoptosis. Seventeen brain distribution components of Kaixinsan were identified. Based on the brain distribution components of Kaixinsan, the results of network pharmacology suggest that Kaixinsan may regulate mitochondrial homeostasis through the CaMKKβ-AMPK-PGC-1α signaling axis. In vivo experiments, The authors observed that Kaixinsan could reverse neuronal mitochondrial loss in SAMP8 mice by upregulating CaMKKβ, AMPK, HSP90 and PGC-1α to promote mitochondrial biogenesis and increase the number of neuronal mitochondria. Additionally, the in vitro experiments demonstrated that Kaixinsan can inhibit apoptosis of Aβ25-35 injured SH-SY5Y cells and upregulate mitochondrial homeostasis-related proteins CaMKKβ, AMPK and PGC-1α. However, in addition to CaMKKβ inhibitors, the neuroprotective effect disappeared. ConclusionThe results indicate that Kaixinsan can improve the cognitive function of SAMP8 mice by regulating CaMKKβ-AMPK-PGC-1α signaling axis to maintain mitochondrial homeostasis and inhibit neuronal apoptosis.

Exploring multitarget potential of Piper nigrum fruit constituents for Alzheimer's disease: An AI-driven strategy

BackgroundAlzheimer's disease (AD) is a neurodegenerative disease that leads to development of cognition and memory dysfunctions. Currently, there is no known cure for AD, although limited medications are approved for the management of disease condition. Various plant-based leads give new hope for considering phytoconstituents as anti-AD drugs. The Piper nigrum L. fruit extract was reported to have anti-Alzheimer's activity. It creates an interest in the finding of active moieties that may be accountable for anti-AD activity. Hypothesis/PurposeIdentification of multitarget directed ligands isolated from Piper nigrum fruits through AI based studies. Study designThe phytochemical analysis of alkaloid fraction was carried out by LCMS, followed by the evaluation of constituents through in silico studies. MethodsThe fruits methanolic extract was prepared by cold maceration technique. The chemical profiling of the alkaloidal fraction was carried out using LCMS/MS analysis. The obtained compound's target hit genes were identified through network pharmacology studies using String, Metascape, and Cytoscape tools. Further, docking studies and MD simulations were carried out using AutoDock4 and Desmond-Maestro software. Then, electrochemical properties of hit compound P4 were determined using Gaussview6 software. ResultsFrom LCMS/MS analysis data, 29 compounds were considered based on compound intensity and accuracy (>95 %). Then, 41 common gene targets were identified from AD genes and compound-targeted genes. The 41 common genes in the PPI network suggested that AChE and BACE1 were the most abundant proteins. Further, docking studies revealed the hit compound P4 binding interaction and energies when compared to other 28 ligands. The molecular dynamics studies showed that P4-AChE and P4-BACE1 complexes were stable, and there were no RMSD and RMSF fluctuations were observed up to 100 ns. Further, PCA and MM-GBSA analysis data supported that complexes (P4-AChE and P4-BACE1) were stable. The DFT and surface properties indicated that compound P4 was ideal candidate for AD treatment and must be considered for further biological activity studies. ConclusionThe study identified compound P4 (dehydropipernonaline) from alkaloidal fraction of Piper nigrum fruits, suggesting it may be hit candidate for AD treatment.

Exploring Caregiver Burden in Alzheimer's Disease: The Predictive Role Of Psychological Distress

Background Alzheimer's Disease [AD], the most prevalent form of dementia, is on the rise in terms of its prevalence. Individuals affected by this condition typically require extensive care across all aspects of daily living. The mental well-being of caregivers for those with dementia stands as a significant public concern. Therefore, the current study aimed to investigate the association between the burden of caregiving and the psychological distress experienced by family caregivers of individuals with AD. Methods This cross-sectional study employed a census method and involved the participation of 150 caregivers of Alzheimer's patients in Shahroud, Iran. To assess the eligibility of family caregivers, the inclusion criteria comprised minimal literacy in reading and writing and at least six months of care for an individual with AD.. Exclusion criteria included being a formal caregiver or employed in healthcare, having mental disorders, or using neuroleptic drugs among family caregivers. Data collection tools consisted of the Zarit Care Burden Inventory [ZBI] and Lovibond's Depression, Anxiety, and Stress Scale [DASS-21]. Information was gathered online and through self-reporting, followed by analysis using descriptive statistics [frequency, percentage, mean, and standard deviation], as well as inferential statistical tests [multivariate linear regression]. Results In this study, the mean scores for caregiver burden, anxiety, stress, and depression were 28.09 ±13.01, 4.50 ±4.53, 8.12 ±4.98, and 4.69 ± 4.86, respectively. The study's findings revealed that with each additional hour spent on daily patient care, the burden score for caregivers increased by 0.327 units [p=0.025, β=0.327]. Furthermore, for every one-unit rise in stress [p<0.001, β=1.087] and depression scores [p=0.015, β=0.671], the burden score also increased by 1.087 and 0.671 units, respectively. Conclusion Caregivers of individuals with AD experienced notable levels of caregiving burden, particularly correlated with the duration of daily patient care and the manifestation of stress and depression symptoms. Hence, the study suggests the implementation of tailored interventions, such as psychoeducational programs, to provide vital support for these individuals.

Exploring the Relationship Between Amyloid Burden and Depression in Pre-clinical Alzheimer's Disease.

Background Alzheimer's disease (AD) is a form of dementia, marked by amyloid-β plaques, neurofibrillary tangles, and neuronal loss. The amyloid burden has been associated with cognitive impairment and depression, suggesting a potential link between these conditions. Objective This study investigates the relationships between amyloid burden, cognitive impairment, and depression in the preclinical stages of AD. Methods Data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study, involving 4486 cognitively unimpaired individuals aged 65-85, was analyzed. The amyloid burden was assessed using positron emission tomography (PET) standardized uptake value ratio (SUVR), cognitive function viacognitive function index (CFI) and tests, and depression via the short-form geriatric depression scale. Mediation analyses, adjusted for age, sex, and education, were employed to measure the impact of amyloid deposition on depression into direct and cognition-mediated indirect effects. Results No significant direct correlation between amyloid burden and depression was found (p=0.2935). Significant indirect effects were observed in cognition measures: CFI (0.3203, 95% CI: (0.2382, 0.4010)), digit symbol substitution test (0.0401, 95% CI: (0.0180, 0.0683)), and immediate recall (0.0169, 95% CI: (0.0014, 0.0354)). However, free and cued selective reminding (0.0056, 95% CI: (-0.0078, 0.0268)) and delayed recall (0.0105, 95% CI: (-0.0009, 0.0259)) showed no significant indirect effects. Conclusions The findings indicate significant mediation by CFI, digit symbol substitution test, and immediate recall in the relationship between amyloid burden and depression while free and cued selective reminding and delayed recall showed no significant mediation. These results underscore the importance of further research using longitudinal data and a broader range of confounders to fully understand cognition's mediating role.

Jiawei Xionggui Decoction promotes meningeal lymphatic vessels clearance of β-amyloid by inhibiting arachidonic acid pathway

BackgroundAlzheimer's disease (AD) is an aging-associated form of dementia characterized by the pathological deposition of toxic misfolded proteins in the central nervous system (CNS), which is closely related to the clearance impairment of meningeal lymphatic vessels (mLVs). Thus, enhancement dural meningeal lymphatic drainage to remove amyloid-β (Aβ) is usually considered as a potential therapeutic target for AD. PurposeThis study aimed to investigate the mechanisms of Jiawei Xionggui Decoction (JWXG) to attenuate cognitive dificits in APP/PS1 mice with impaired meningeal lymphatic drainage. MethodsLigation of deep cervical lymph nodes (dcLNs) was performed to establish the mice model of the impaired meningeal lymphatic drainage in APP/PS1 mice. Cognitve behaviors and pathological morphology of mice were assessed. Cerebral blood flow (CBF) of mice was determined using Laser speckle contrast imaging analysis. Serum non-targeted metabolomics analysis was applied to decipher the mechanisms of JWXG in rescuing the impairment of mLVs, and C8-D1A cells were employed to validate in vitro. ResultsDisruption of mLVs in APP/PS1 mice deteriorated cognitive dysfunction, accelerated Aβ burden and glia activation, accompanied by more severe neuropathological damage, CBF reduction and neuroinflammation exacerbation. Serum non-targeted metabolomics analysis indicates the increase of arachidonic acid (AA) metabolic pathway was the key contributor to the neuropathological exacerbation of dcLNs ligation APP/PS1 mice. Interestingly, clinically equivalent dose of JWXG was sufficient to restore mLVs drainage and rescue cognitive performance by inhibiting neuroinflammation depended by AA metabolic pathway in dcLNs ligation APP/PS1 mice. ConclusionOur findings establish a novel mechanism that rescue mLVs by inhibiting AA metabolic pathway to clear brain Aβ, and support JWXG as a feasible treatment strategy for AD by suppressing AA metabolic pathway to improve mLVs drainage efficiency.

Interactions between mild depressive symptoms and amyloid pathology on the trajectory of neurodegeneration, cognitive decline, and risk of Alzheimer's disease

BackgroundAlzheimer's disease (AD) was driven by the interplay between modifiable environmental factors and β-amyloid (Aβ) pathology. We aimed to investigate the interaction effects of mild depressive symptoms (MDS) with Aβ on AD development. MethodsLongitudinal data of 1746 non-demented adults (mean age = 73 years, female = 53 %, maximum = 10 years) were derived from the Alzheimer's Disease Neuroimaging Initiative cohort. MDS was separately defined by the baseline status, longitudinal latent class, and average intensity during follow-up. Amyloid-positive (A+) status was determined based on cerebrospinal fluid levels of β-amyloid. Regression models were employed to analyze the interactive effects of MDS with A+ on cognitive decline, neurodegeneration, and AD incidence. ResultsIndividuals with both A+ status and MDS at baseline experienced the fastest neurodegeneration (p < 0.01), cognitive decline (p < 0.05), and a higher risk of developing AD (HR = 5.23, p < 0.001). Furthermore, A+ participants with the trajectory of increasing depressive symptoms demonstrated more pronounced neurodegeneration (p < 0.001), cognitive decline (p < 0.01), and elevated risk of AD (HR = 10.45, p < 0.001). Finally, A+ status in combination with a higher average intensity of depressive symptoms was associated with faster brain atrophy (p < 0.01) and brain metabolism decline (p < 0.05), cognitive decline (p < 0.05), and higher AD risk (HR = 13.99, p < 0.001). ConclusionThese findings emphasized that the MDS-Aβ interaction relationship should be considered in risk stratification, prediction, and early management of neurodegeneration and cognitive decline in the pre-dementia stage.

Interplay of MeCP2/REST/Synaptophysin-BDNF and intranasal oxytocin influence on Aβ-induced memory and cognitive impairments

BackgroundAlzheimer's disease (AD) is linked to the accumulation of Aβ, increased tau hyperphosphorylation, persistent neuroinflammation, and a decline in neurotrophic factors, neurogenesis, and synaptic plasticity. Oxytocin (OT) has a significant impact on memory and learning. We examined the influence of intranasal (IN) OT on synaptic plasticity, neurogenesis, histone acetylation, and spatial and cognitive memories in rats. MethodsAβ25–35 (5 µg/2.5 µl) was administered bilaterally in the CA1 of male Wistar rats for four consecutive days. After seven days of recovery, OT (2 µg/µl, 10 µl in each nostril) was administered IN for seven consecutive days. Working, spatial, and cognitive memories, and gene expression of neurogenesis- and synaptic plasticity-involved factors were measured in the hippocampus. Histone acetylation (H3K9 and H4K8) was also measured using western blotting. ResultsIN administration of OT significantly improved working and spatial memory impairment induced by Aβ and increased the factors involved in synaptic plasticity (MeCP2, REST, synaptophysin, and BDNF) and neurogenesis (Ki67 and DCX). We also found an enhancement in the levels of H3K9ac and H4K8ac following OT administration. ConclusionThese findings indicated that IN OT could improve hippocampus-related behaviors by increasing synaptic plasticity, stimulating neurogenesis, and chromatin plasticity.

Icariin targets p53 to protect against ceramide-induced neuronal senescence: Implication in Alzheimer's disease

BackgroundAlzheimer's disease (AD) is a leading cause of dementia. The aging brain is particularly vulnerable to various stressors, including increased levels of ceramide. However, the role of ceramide in neuronal cell senescence and AD progression and whether icariin, a natural flavonoid glucoside, could reverse neuronal senescence remain inadequately understood. AimIn this study, we explore the role of ceramide in neuronal senescence and AD, and whether icariin can counteract these effects. MethodsWe pretreated HT-22 cells with icariin and then induced senescence with ceramide. Various assays were employed to assess cell senescence, such as reactive oxygen species (ROS) production, cell cycle progression, β-galactosidase staining, and expression of senescence-associated proteins. In vivo studies utilized APP/PS1 mice and C57BL/6J mice injected with ceramide to evaluate behavioral changes, histopathological alterations, and senescence-associated protein expression. Transcriptomics, molecular docking, molecular dynamics simulations, and cellular thermal shift assays were employed to verify the interaction between icariin and P53. The specificity of icariin targeting of P53 was further confirmed through rescue experiments utilizing the P53 activator Navtemadlin. ResultsOur data demonstrated that ceramide could induce neuronal senescence and AD-related pathologies, which were reversed by icariin. Moreover, molecular studies revealed that icariin directly targeted P53, and its neuroprotective effects were attenuated by P53 activation, providing evidence for the role of P53 in icariin-mediated neuroprotection. ConclusionIcariin demonstrates a protective effect against ceramide-induced neuronal senescence by inhibiting the P53 pathway. This identifies a novel mechanism of action for icariin, offering a novel therapeutic approach for AD and other age-related neurodegenerative diseases.

High-intensity body weight interval training modifies neurochemistry in AD disease: Preliminary data from a randomized control trial

BackgroundAlzheimer's disease (AD) is an incurable condition characterized by cognitive and neurochemical impairments, necessitating the exploration of alternative interventions. Physical exercise shows promise, but the effects of high-intensity protocols on the neurochemical aspects of AD-related neurodegeneration remain poorly explored. ObjectiveThis study examines the effects of high-intensity body weight interval training (PMED) on brain-derived neurotrophic factor (BDNF) and phosphorylated-TAU protein (p-TAU) in AD disease. MethodsThirty-four elderly individuals diagnosed with AD disease were divided into two groups of 17 subjects: GCP, which participated in PMED (30 min at 80–90 % of maximal cardiac frequency three times per week), and GCS, which had no interventions. Pre- and post-measurements of BDNF and p-TAU were conducted. ResultsThe GCS group showed no changes in his neurochemical factors (p > 0.05). In contrast, the GCP group experienced increased BDNF levels and decreased p-TAU blood concentrations (p < 0.0001 for both). ConclusionsPMED increased BDNF and reduced p-TAU concentrations, improving neurochemistry in AD disease. This can open an avenue of new interventions using high-intensity body weight interval training, including, in home base programs, which can be an advantage to engagement.

Alzheimer's disease with depressive symptoms: Clinical effect of intermittent theta burst stimulation repetitive transcranial magnetic stimulation

BACKGROUND Alzheimer's disease (AD), characterized by the ongoing deterioration of neural function, often presents alongside depressive features and greatly affects the quality of life of individuals living with the condition. Although several treatment methods exist, their efficacy is limited. In recent years, repetitive transcranial magnetic stimulation (rTMS) utilizing the theta burst stimulation (TBS) mode, specifically the intermittent TBS (iTBS), has demonstrated promising therapeutic potential in the management of neuropsychiatric disorders. AIM To examine the therapeutic efficacy of iTBS mode of rTMS for treating depressive symptoms in patients with AD. METHODS This retrospective study enrolled 105 individuals diagnosed with AD with depressive symptoms at Huzhou Third Municipal Hospital, affiliated with Huzhou University, between January 2020 and December 2023. Participants received standard pharmacological interventions and were categorized into control (n = 53) and observation (n = 52) groups based on treatment protocols. The observation group received iTBS mode of rTMS, while the control group received pseudo-stimulation. A comparative analysis evaluated psychological well-being, adverse events, and therapeutic at initiation of hospitalization (T0) and 15 days post-treatment (T1). RESULTS At T1, both groups exhibited a marked reduction in self-rating depression scale and Hamilton depression scale scores compared to T0. Furthermore, the observation group showed a more pronounced decrease than the control group. By T1, the Mini-mental state examination scores for both groups had increased markedly from their initial T0 assessments. Importantly, the increase was particularly more substantial in the observation group than in the control group. Fourteen patients in the control group had ineffective treatment effects, while five patients in the observation group experienced the same. Additionally, the observation group experienced a substantially reduced incidence of ineffective treatment as compared to the control group (both P &lt; 0.05); there were no recorded serious adverse events in either group. CONCLUSION The iTBS model of rTMS effectively treated AD with depression, improving depressive symptoms and cognitive function in patients without serious adverse reactions, warranting clinical consideration.

Plasma lipidomics in early APP/PS1 female mouse model and its relationship with brain: Is it affected by the estrous cycle?

BackgroundAlzheimer's disease (AD) is the most prevalent dementia, showing higher incidence in women. Besides, lipids play an essential role in brain, and they could be dysregulated in neurodegeneration. Specifically, impaired plasma lipid levels could predict early AD diagnosis. This work aims to identify the main plasma lipids altered in early AD female mouse model and evaluate their relationship with brain lipidome. Also, the possible involvement of the estrous cycle in lipid metabolism has been evaluated.MethodsPlasma samples of wild-type (n = 10) and APP/PS1 (n = 10) female mice of 5 months of age were collected, processed, and analysed using a lipidomic mass spectrometry-based method. A statistical analysis involving univariate and multivariate approaches was performed to identify significant lipid differences related to AD between groups. Also, cytology tests were conducted to confirm estrous cycle phases.ResultsThree hundred thirty lipids were detected in plasma, 18 of them showed significant differences between groups; specifically, some triacylglycerols, cholesteryl esters, lysophosphatidylcholines, phosphatidylcholines, and ether-linked phosphatidylcholines, increased in early AD; while other phosphatidylcholines, phosphatidylethanolamines, ceramides, and ether-linked phosphatidylethanolamines decreased in early AD. A multivariate approach was developed from some lipid variables, showing high diagnostic indexes (70% sensitivity, 90% specificity, 80% accuracy). From brain and plasma lipidome, some significant correlations were observed, mainly in the glycerophospholipid family. Also, some differences were found in both plasma and brain lipids, according to the estrous cycle phase.ConclusionsTherefore, lipid alterations can be identified in plasma at early AD stages in mice females, with a relationship with brain lipid metabolism for most of the lipid subfamilies, suggesting some lipids as potential AD biomarkers. In addition, the estrous cycle monitoring could be relevant in female studies.

Human brain organoids containing microglia that have arisen innately adapt to a β-amyloid challenge better than those in which microglia are integrated by co-culture

BackgroundAlzheimer disease (AD) is a heterogenous and multifactorial disease, and its pathology is partly driven by microglia and their activated phenotype. Brain organoids (BOs) are gaining prominence as a relevant model of the human brain for the study of AD; however, BOs are commonly devoid of microglia. To overcome this limitation, current protocols incorporate microglia through either (1) co-culture (BO co-culture), or (2) molecular manipulation at critical windows of BO development to have microglia arise innately (BO innate cultures). It is currently unclear whether the microglia incorporated into BOs by either of these two protocols differ in function.MethodsAt in vitro day 90, BO innate cultures and BO-co-cultures were challenged with the AD-related β-amyloid peptide (Aβ) for up to 72 h. After Aβ challenge, BOs were collected for immunoblotting. Immunoblots compared immunodensity and protein banding of Aβ and ionized calcium-binding adapter molecule 1 (IBA1, a marker of microglial activation) in BOs. The translational potential of these observations was supported using 56 human cortical samples from neurocognitively normal donors and patients with early-onset AD and late-onset AD. Statistical analyses were conducted using the Kruskal–Wallis test, a two-way ANOVA, or a simple linear regression, and where applicable, followed by Dunn’s or Sidak’s test.ResultsWe show that BO co-cultures promote Aβ oligomerization as early as 24 h and this coincides with a significant increase in IBA1 levels. In contrast, the Aβs do not oligomerize in BO innate cultures and the IBA1 response was modest and only emerged after 48 h. In human cortical samples, we found IBA1 levels correlated with age at onset, age at death, and the putative diagnostic Aβ(1–42)/Aβ(1–40) ratio (particularly in their oligomeric forms) in a sex-dependent manner.ConclusionsOur unique observations suggest that BOs with innate microglia model the response of a healthy brain to Aβ, and by extension the initial stages of Aβ challenge. It would be impossible to model these early stages of pathogenesis in BOs where microglia are already compromised, such as those with microglia incorporated by co-culture.

Psychological distress among family caregivers of persons with Alzheimer’s disease and related dementias in Uganda

BackgroundAlzheimer's disease and related dementias (ADRD) present growing global health challenges, especially in aging populations, such as Uganda. In Uganda, familial caregiving, predominantly undertaken by female relatives, is the primary form of support provided to patients with ADRD. Cultural stigma around dementia and limited access to support services amplify caregivers' challenges. This study examined psychological distress, depression, and quality of life (QoL) among family caregivers of patients with ADRD in Wakiso District, Uganda.MethodsThis cross-sectional study involved 90 caregivers from three sub-counties in Wakiso, selected through purposive sampling to capture diverse experiences. Participants included caregivers aged 18 years and older who were knowledgeable and had cared for a person with ADRD for not less than six months, with those providing more than 70% of physical care being prioritised. Data were collected using the Kessler Psychological Distress Scale, the Caregiver Dementia Quality of Life Measurement Scale, and the Center for Epidemiologic Studies Depression Scale, with an 80% response rate achieved through local collaboration. The statistical analyses focused on psychological distress, QoL, and depression.ResultsThe study included 82.2% females and 17.8% males, with a median age of 52 years for females and 35 years, respectively. Females were more likely to be single or widowed, whereas males were more likely to be married. The study revealed a high prevalence of psychological distress and depression among caregivers (64.4%) regardless of sex. The analysis indicated that having children was a significant predictor of better QoL (OR 3.04, 95% CI 1.79–5.66, p = 0.034) and a lower risk of depression (OR 0.10, 95% CI 0.01–0.86, p = 0.036). No other sociodemographic factors were significantly associated with health outcomes across the models.ConclusionOur findings revealed a heavy burden of psychological distress and depression among Ugandan caregivers of patients with ADRD, highlighting the need for structured support systems, including mental health services and gender-responsive interventions in low-resource settings.

Enhancing Classification of Alzheimer’s Disease using Spatial Attention Mechanism

Aim This study aims to enhance the precision of Alzheimer's disease (AD) detection by integrating Spatial Attention Mechanism into a Convolutional Neural Network (CNN) architecture. Background Alzheimer's disease is a progressive neurodegenerative disorder characterized by abnormal protein deposits in the brain, leading to nerve cell loss and posing a significant global health challenge. Early and accurate detection is crucial for disease management and treatment due to the lack of a cure and the disease's severe progression. Objective The objective of this research is to improve the accuracy of Alzheimer's disease classification using MRI data by implementing a Spatial Attention Mechanism in a CNN architecture. Methods The study utilized T1-weighted MRI data from the OASIS 1 and OASIS 2 datasets. The key innovation is the Spatial Attention layer incorporated within a CNN model, which computes the average of each channel in the input feature map. This layer guides subsequent layers to focus on critical brain regions, enhancing the model's accuracy in differentiating between Alzheimer's disease stages. Results The model achieved a validation accuracy of 99.69% with a sensitivity and specificity of 1.0000, demonstrating its reliability in distinguishing between different stages of Alzheimer's disease. The adaptability of the Spatial Attention layer allows the model to assign higher weights to crucial brain regions, improving its discriminative power. Conclusion The integration of the Spatial Attention Mechanism into the CNN architecture significantly contributes to the early detection of Alzheimer's disease, enabling timely interventions. This innovative approach has the potential to revolutionize Alzheimer's diagnosis by enhancing accuracy and offering a robust solution for classification.

Anti-oxidative stress and cognitive improvement of a semi-synthetic isoorientin-based GSK-3β inhibitor in rat pheochromocytoma cell PC12 and scopolamine-induced AD model mice via AKT/GSK-3β/Nrf2 pathway

BackgroundAlzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive deficits. Although the pathogenesis of AD is unclear, oxidative stress has been implicated to play a dominant role in its development. The flavonoid isoorientin (ISO) and its synthetic derivatives TFGF-18 selectively inhibit glycogen synthase kinase-3β (GSK-3β), a potential target of AD treatment. PurposeTo investigate the neuroprotective effect of TFGF-18 against oxidative stress via the GSK-3β pathway in hydrogen peroxide (H2O2)-induced rat pheochromocytoma PC12 cells in vitro and scopolamine (SCOP)-induced AD mice in vivo. MethodThe oxidative stress of PC12 cells was induced by H2O2 (600 μM) and the effects of TFGF-18 (2 and 8 μM) or ISO (12.5 and 50 μM) were observed. The AD mouse model was induced by SCOP (3 mg/kg), and the effects of TFGF-18 (2 and 8 mg/kg), ISO (50 mg/kg), and donepezil (DNP) (3 mg/kg) were observed. DNP, a currently accepted drug for AD was used as a positive control. The neuronal cell damages were analyzed by flow cytometry, LDH assay, JC-1 assay and Nissl staining. The oxidative stress was evaluated by the detection of MDA, SOD, GPx and ROS. The level of ACh, and the activity of AChE, ChAT were detected by the assay kit. The expressions of Bax, Bcl-2, caspase3, cleaved-caspase3, p-AKT (Thr308), AKT, p-GSK-3β (Ser9), GSK-3β, Nrf2, and HO-1, as well as p-CREB (Ser133), CREB, and BDNF were analyzed by western blotting. Morris water maze test was performed to analyze learning and memory ability. ResultsTFGF-18 inhibited neuronal damage and the expressions of Bax, caspase3 and cleaved-caspase3, and increased the expression of Bcl-2 in vitro and in vivo. The level of MDA and ROS were decreased while the activities of SOD and GPx were increased by TFGF-18. Moreover, TFGF-18 increased the p-AKT, p-GSK-3β (Ser9), Nrf2, HO-1, p-CREB, and BDNF expression reduced by H2O2 and SCOP. Meanwhile, MK2206, an AKT inhibitor, reversed the effect of TFGF-18 on the AKT/GSK-3β pathway. In addition, the cholinergic system (ACh, ChAT, and AChE) disorders were retrained and the learning and memory impairments were prevented by TFGF-18 in SCOP-induced AD mice. ConclusionsTFGF-18 protects against neuronal cell damage and cognitive impairment by inhibiting oxidative stress via AKT/GSK-3β/Nrf2 pathway.

Rhei Undulati Rhizoma attenuates memory decline and reduces amyloid-β induced neuritic dystrophy in 5xFAD mouse

BackgroundAlzheimer's disease (AD) is a common type of dementia characterized by amyloid-β (Aβ) accumulation, lysosomal dysfunction, and tau hyperphosphorylation, leading to neurite dystrophy and memory loss. This study aimed to investigate whether Rhei Undulati Rhizoma (RUR), which has been reported to have anti-neuroinflammatory effect, attenuates Aβ-induced memory impairment, neuritic dystrophy, and tau hyperphosphorylation, and to reveal its mode of action.MethodsFive-month-old 5xFAD mice received RUR (50 mg/kg) orally for 2 months. The Y-maze test was used to assess working memory. After behavioral testing, brain tissue was analyzed using thioflavin S staining, western blotting, and immunofluorescence staining to investigate the mode of action of RUR. To confirm whether RUR directly reduces Aβ aggregation, a thioflavin T assay and dot blot were performed after incubating Aβ with RUR.ResultsRUR administration attenuated the Aβ-induced memory impairment in 5xFAD mice. Furthermore, decreased accumulation of Aβ was observed in the hippocampus of the RUR-treated 5xFAD group compare to the vehicle-treated 5xFAD group. Moreover, RUR reduced the dystrophic neurites (DNs) that accumulate impaired endolysosomal organelles around Aβ. In particular, RUR treatment downregulated the expression of β-site amyloid precursor protein cleaving enzyme 1 and the hyperphosphorylation of tau within DNs. Additionally, RUR directly suppressed the aggregation of Aβ, and eliminated Aβ oligomers in vitro.ConclusionsThis study showed that RUR could attenuate Aβ-induced pathology and directly regulate the aggregation of Aβ. These results suggest that RUR could be an efficient material for AD treatment through Aβ regulation.Graphical