Alzheimer's Disease Pathogenesis Research Articles

Association between retinal microvascular abnormalities and late-life brain amyloid-β deposition: the ARIC-PET study

BackgroundRetinal microvascular signs are accessible measures of early alterations in microvascular dysregulation and have been associated with dementia; it is unclear if they are associated with AD (Alzheimer’s disease) pathogenesis as a potential mechanistic link. This study aimed to test the association of retinal microvascular abnormalities in mid and late life and late life cerebral amyloid.MethodsParticipants from the ARIC‐PET (Atherosclerosis Risk in Communities‐Positron Emission Tomography) study with a valid retinal measure (N = 285) were included. The associations of mid- and late-life retinal signs with late-life amyloid-β (Aβ) by florbetapir PET were tested. Two different measures of Aβ burden were included: (1) elevated amyloid (SUVR > 1.2) and (2) continuous amyloid SUVR. The retinal measures’ association with Aβ burden was assessed using logistic and robust linear regression models. A newly created retinal score, incorporating multiple markers of retinal abnormalities, was also evaluated in association with greater Aβ burden.ResultsRetinopathy in midlife (OR (95% CI) = 0.36 (0.08, 1.40)) was not significantly associated with elevated amyloid burden. In late life, retinopathy was associated with increased continuous amyloid standardized value uptake ratio (SUVR) (β (95%CI) = 0.16 (0.02, 0.32)) but not elevated amyloid burden (OR (95%CI) = 2.37 (0.66, 9.88)) when accounting for demographic, genetic and clinical risk factors. A high retinal score in late life, indicating a higher burden of retinal abnormalities, was also significantly associated with increased continuous amyloid SUVR (β (95% CI) = 0.16 (0.04, 0.32)) independent of vascular risk factors.ConclusionsRetinopathy in late life may be an easily obtainable marker to help evaluate the mechanistic vascular pathway between retinal measures and dementia, perhaps acting via AD pathogenesis. Well-powered future studies with a greater number of retinal features and other microvascular signs are needed to test these findings.

EPB41L4A-AS1 is required to maintain basal autophagy to modulates Aβ clearance

Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by the deposition of β-amyloid (Aβ) plaques. Aβ is generated from the cleavage of the amyloid precursor protein by β and γ-secretases and cleared by neuroglial cells mediated autophagy. The imbalance of the intracellular Aβ generation and clearance is the causative factor for AD pathogenesis. However, the exact underlying molecular mechanisms remain unclear. Our previous study reported that EPB41L4A-AS1 is an aging-related long non-coding RNA (lncRNA) that is repressed in patients with AD. In this study, we found that downregulated EPB41L4A-AS1 in AD inhibited neuroglial cells mediated-Aβ clearance by decreasing the expression levels of multiple autophagy-related genes. We found that EPB41L4A-AS1 regulates the expression of general control of amino acid synthesis 5-like 2, an important histone acetyltransferase, thus affecting histone acetylation, crotonylation, and lactylation near the transcription start site of autophagy-related genes, ultimately influencing their transcription. Collectively, this study reveals EPB41L4A-AS1 as an AD-related lncRNA via mediating Aβ clearance and provides insights into the epigenetic regulatory mechanism of EPB41L4A-AS1 in gene expression and AD pathogenesis.

Is There a Role of Vitamin D in Alzheimer's Disease?

Alzheimer's disease (AD) represents the most prevalent type of neurodegenerative dementia and the sixth leading cause of death worldwide. The so-called "non-calcemic actions" of vitamin D have been increasingly described, and its insufficiency has already been linked to the onset and progression of the main neurological diseases, including AD. Immune-mediated Aβ plaque's phagocytosis and clearance, immune response, oxidative stress, and mitochondrial function are all influenced by vitamin D, and these functions are considered relevant in AD pathogenesis. However, it has been shown that the genomic vitamin D signaling pathway is already impaired in the AD brain, making things more complicated. In this paper, we aim to summarise the role of vitamin D in AD and review the results of the supplementation trials in AD patients.

Hiding in plain sight: Do recruited dendritic cells surround amyloid plaques in alzheimer's disease?

Over the past decade, human genome-wide association and expression studies have strongly implicated dysregulation of the innate immune system in the pathogenesis of Alzheimer's disease (AD). Single cell mRNA sequencing studies have identified innate immune cell subtypes that are minimally present in normal healthy brain, but whose numbers greatly increase in association with AD pathology. These AD pathology-associated immune cells are putatively the locus for the immune-related AD risk. While the prevailing view is that these immune cells arise from transformation of resident brain microglia, studies across several decades and using multiple techniques and strategies suggest instead that the pathology-associated immune cells are bone-marrow derived hematopoietic cells that are recruited into brain. We critically review this translational literature, emphasizing the strengths and limitations of techniques used to address recruitment and the experimental designs employed. We conclude that the aggregate evidence points toward recruitment into brain of innate immune cells of the myeloid dendritic cell lineage. Recruitment of dendritic cells and their role in AD pathogenesis has broad implications for our understanding of the etiology and pathobiology of AD that impact the strategies to develop new, immune system-targeted therapeutics for this devastating disease.

Penthorum chinense Pursh inhibits ferroptosis in cellular and Caenorhabditis elegans models of Alzheimer's disease

Background: Ferroptosis, a unique type of cell death triggered by iron-dependent lipid peroxidation, plays a critical role in the pathogenesis of Alzheimer's disease (AD), a debilitating condition marked by memory loss and cognitive impairment due to the accumulation of beta-amyloid (Aβ) and hyperphosphorylated Tau protein. Increasing evidence suggests that inhibitors of ferroptosis could be groundbreaking in the treatment of AD. Method: In this study, we established in vitro ferroptosis using erastin-, RSL-3-, hemin-, and iFSP1-induced PC-12 cells. Using MTT along with Hoechst/PI staining, we assessed cell viability and death. To determine various aspects of ferroptosis, we employed fluorescence probes, including DCFDA, JC-1, C11 BODIPY, Mito-Tracker, and PGSK, to measure ROS production, mitochondrial membrane potential, lipid peroxidation, mitochondrial morphology, and intracellular iron levels. Additionally, Western blotting, biolayer interferometry technology, and shRNA were utilized to investigate the underlying molecular mechanisms. Furthermore, p-CAX APP Swe/Ind- and pRK5-EGFP-Tau P301L overexpressing PC-12 cells, along with Caenorhabditis elegans (C. elegans) strains CL4176, CL2331, and BR5270, were employed to examine ferroptosis in AD models. Results: Here, we conducted a screening of our natural medicine libraries and identified the ethanol extract of Penthorum chinense Pursh (PEE), particularly its ethyl acetate fraction (PEF), displayed inhibitory effects on ferroptosis in cells. Specifically, PEF inhibited the generation of ROS, lipid peroxidation, and intracellular iron levels. Furthermore, PEF demonstrated protective effects against H2O2-induced cell death, ROS production, and mitochondrial damage. Mechanistic investigations unveiled PEF's modulation of intracellular iron accumulation, GPX4 expression and activity, and FSP1 expression. In p-CAX APP Swe/Ind and pRK5-EGFP-Tau P301L overexpressing PC-12 cells, PEF significantly reduced cell death, as well as ROS and lipid peroxidase production. Moreover, PEF ameliorated paralysis and slowing rate in Aβ and Tau transgenic C. elegans models, while inhibiting ferroptosis, as evidenced by decreased DHE intensity, lipid peroxidation levels, iron accumulation, and expression of SOD-3 and gst-4. Conclusion: Our findings highlight the suppressive effects of PEF on ferroptosis in AD cellular and C. elegans models. This study helps us better understand how ferroptosis affects AD and emphasizes the potential of PCP as a candidate for AD intervention.

The broken Alzheimer's disease genome.

The complex pathobiology of late-onset Alzheimer's disease (AD) poses significant challenges to therapeutic and preventative interventions. Despite these difficulties, genomics and related disciplines are allowing fundamental mechanistic insights to emerge with clarity, particularly with the introduction of high-resolution sequencing technologies. After all, the disrupted processes at the interface between DNA and gene expression, which we call the broken AD genome, offer detailed quantitative evidence unrestrained by preconceived notions about the disease. In addition to highlighting biological pathways beyond the classical pathology hallmarks, these advances have revitalized drug discovery efforts and are driving improvements in clinical tools. We review genetic, epigenomic, and gene expression findings related to AD pathogenesis and explore how their integration enables a better understanding of the multicellular imbalances contributing to this heterogeneous condition. The frontiers opening on the back of these research milestones promise a future of AD care that is both more personalized and predictive.

Reduction in Constitutively Activated Auditory Brainstem Microglia in Aging and Alzheimer's Disease.

Alzheimer's disease (AD) pathology is considered to begin in the brainstem, and cerebral microglia are known to play a critical role in AD pathogenesis, yet little is known about brainstem microglia in AD. Translocator protein (TSPO) PET, sensitive to activated microglia, shows high signal in dorsal brainstem in humans, but the precise location and clinical correlates of this signal are unknown. To define age and AD associations of brainstem TSPO PET signal in humans. We applied new probabilistic maps of brainstem nuclei to quantify PET-measured TSPO expression over the whole brain including brainstem in 71 subjects (43 controls scanned using 11C-PK11195; 20 controls and 8 AD subjects scanned using 11C-PBR28). We focused on inferior colliculi (IC) because of visually-obvious high signal in this region, and potential relevance to auditory dysfunction in AD. We also assessed bilateral cortex. TSPO expression was normally high in IC and other brainstem regions. IC TSPO was decreased with aging (p = 0.001) and in AD subjects versus controls (p = 0.004). In cortex, TSPO expression was increased with aging (p = 0.030) and AD (p = 0.033). Decreased IC TSPO expression with aging and AD-an opposite pattern than in cortex-highlights underappreciated regional heterogeneity in microglia phenotype, and implicates IC in a biological explanation for strong links between hearing loss and AD. Unlike in cerebrum, where TSPO expression is considered pathological, activated microglia in IC and other brainstem nuclei may play a beneficial, homeostatic role. Additional study of brainstem microglia in aging and AD is needed.

Osteoclasts Link Dysregulated Peripheral Degradation Processes and Accelerated Progression in Alzheimer's Disease.

The amyloid-β (Aβ) enhances the number and activity of blood monocyte-derived osteoclasts (OCs). Individuals with osteoporosis (OP) face an increased risk of developing dementia or Alzheimer's disease (AD). Despite this association, the contribution of bone-resorbing OCs to the progression of AD pathology remains unclear. Our objective was to investigate the potential impacts of OCs on the development of AD pathology. We conducted targeted analysis of publicly available whole blood transcriptomes from patients with AD to characterize the blood molecular signatures and pathways associated with hyperactive OCs. In addition, we used APP23 transgenic (APP23 TG) AD mouse model to assess the effects of OCs pharmacological blockade on AD pathology and behavior. Patients with AD exhibited increased osteoclastogenesis signature in their blood cells, which appears to be positively correlated with dysfunction of peripheral clearance of Aβ mediated by immune cells. Long-term anti-resorptive intervention with Alendronate inhibited OC activity in APP23 mice, leading to improvements in peripheral monocyte Aβ-degrading enzyme expression, Aβ-deposition, and memory decline. Our findings suggest that OCs have a disease-promoting role in the development and progression of AD, possibly linked to their modulation of peripheral immunity. These findings guide future research to further elucidate the connection between OP and AD pathogenesis, highlighting the potential benefits of preventing OP in alleviating cognitive burden.

Selective orexin 2 receptor blockade alleviates cognitive impairments and the pathological progression of Alzheimer's disease in 3xTg-AD mice.

The orexin system is closely related to the pathogenesis of Alzheimer's disease (AD). Orexin-A aggravates cognitive dysfunction and increases amyloid β (Aβ) deposition in AD model mice, but studies of different dual orexin receptor (OXR) antagonists in AD have shown inconsistent results. Our previous study revealed that OX1R blockade aggravates cognitive deficits and pathological progression in 3xTg-AD mice, but the effects of OX2R and its potential mechanism in AD have not been reported. In the present study, OX2R was blocked by oral administration of the selective OX2R antagonist MK-1064, and the effects of OX2R blockade on cognitive dysfunction and neuropsychiatric symptoms in 3xTg-AD mice were evaluated via behavioral tests. Then, immunohistochemistry, western blotting and ELISA were used to detect Aβ deposition, tau phosphorylation and neuroinflammation, and electrophysiological and wheel-running activity recording were recorded to observe hippocampal synaptic plasticity and circadian rhythm. The results showed that OX2R blockade ameliorated cognitive dysfunction, improved LTP depression, increased the expression of PSD-95, alleviated anxiety- and depression-like behaviors and circadian rhythm disturbances in 3xTg-AD mice, and reduced Aβ pathology, tau phosphorylation and neuroinflammation in the brains of 3xTg-AD mice. These results indicated that chronic OX2R blockade exerts neuroprotective effects in 3xTg-AD mice by reducing AD pathology at least partly through improving circadian rhythm disturbance and the sleep-wake cycle and that OX2R might be a potential target for the prevention and treatment of AD; however, the potential mechanism by which OX2R exerts neuroprotective effects on AD needs to be further investigated.

Behavioral and Metabolic Effects of ABCG4 KO in the APPswe,Ind (J9) Mouse Model of Alzheimer’s Disease

The pathogenesis of Alzheimer’s disease (AD) is complex and involves an imbalance between production and clearance of amyloid-ß peptides (Aß), resulting in accumulation of Aß in senile plaques. Hypercholesterolemia is a major risk factor for developing AD, with cholesterol shown to accumulate in senile plaques and increase production of Aß. ABCG4 is a member of the ATP-binding cassette transporters predominantly expressed in the CNS and has been suggested to play a role in cholesterol and Aß efflux from the brain. In this study, we bred Abcg4 knockout (KO) with the APPSwe,Ind (J9) mouse model of AD to test the hypothesis that loss of Abcg4 would exacerbate the AD phenotype. Unexpectedly, no differences were observed in novel object recognition (NOR) and novel object placement (NOP) behavioral tests, or on histologic examinations of brain tissues for senile plaque numbers. Furthermore, clearance of radiolabeled Aß from the brains did not differ between Abcg4 KO and control mice. Metabolic testing by indirect calorimetry, glucose tolerance test (GTT), and insulin tolerance test (ITT) were also mostly similar between groups with only a few mild metabolic differences noted. Overall, these data suggest that the loss of ABCG4 did not exacerbate the AD phenotype.

Systemic inflammation in Aβ1-40-induced Alzheimer’s disease model: New translational opportunities

Alzheimer disease (AD) is the most frequent cause of dementia, and the most common neurodegenerative disease, which is characterized by memory impairment, neuronal death, and synaptic loss in the hippocampus. Sporadic late-onset AD, which accounts for over 95 % of disease cases, is a multifactorial pathology with complex etiology and pathogenesis. Nowadays, neuroinflammation is considered the third most important component of AD pathogenesis in addition to amyloid peptide generation and deposition. Neuroinflammation is associated with the impairment of blood–brain barrier and leakage of inflammatory mediators into the periphery with developing systemic inflammatory responses. Systemic inflammation is currently considered one of the therapeutic targets for AD treatment, that necessitates in-depth study of this phenomenon in appropriate non-transgenic animal models. This study was aimed to explore systemic inflammatory manifestations in rats with Aβ1-40-induced AD. The impairment of spatial memory and cognitive flexibility in Aβ1-40-lesioned rats was accompanied by pronounced systemic inflammation, which was confirmed by commonly accepted biomarkers: increased hematological indices of systemic inflammation (NLR, dNLR, LMR, PLR and SII), signs of anemia of inflammation or chronic diseases, and pro-inflammatory polarized activation of circulating phagocytes. In addition, markers of systemic inflammation strongly correlated with disorders of remote cognitive flexibility in Aβ1-40-lesioned rats. These results indicate, that Aβ1-40-induced AD model permits the investigation of specific element of the disease – systemic inflammation in addition to well reproduced neuroinflammation and impairment of spatial memory and cognitive flexibility. It increases translational value of this well-known model.

The Association of Circulating Glucagon-Like Peptide-1 with Cognitive Functions and Biomarkers in Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disease that is clinically characterized by progressive cognitive decline. Glucagon-like peptide-1 (GLP-1) is a hormone that belongs to the incretin family and is released in response to nutrient intake. It plays a role in maintaining metabolic homeostasis and has been suggested to be involved in maintaining the brain microenvironment. However, the role of GLP-1 in AD pathogenesis has not been fully illustrated. This study aims to investigate the clinical relevance of GLP-1 in AD and the effects of GLP-1 in amyloid-β (Aβ) metabolism in vitro. In this study, 39 AD patients and 120 cognitively intact controls were included. Plasma levels of GLP-1 were measured using ELISA. SH-SY5Y cells overexpressing human amyloid precursor protein (APP) were treated with GLP-1. Western blot analysis was used to assess the effects of GLP-1 on the metabolism of Aβ. Plasma GLP-1 levels were decreased with aging. Plasma GLP-1 levels were lower in AD patients in comparison with healthy older adults. Plasma GLP-1 levels were positively associated with Mini-Mental State Examination scores but negatively associated with plasma pTau181 levels. GLP-1 dose-dependently increased the area fraction of mitochondrial staining in vitro. Furthermore, GLP-1 dose-dependently promoted the α-cleavage of APP, thus reducing the generation of Aβ. GLP-1 has neuroprotective effects in AD, and therefore the decrease in GLP-1 levels during aging might contribute to the development of AD.

Ginkgo biloba and Its Chemical Components in the Management of Alzheimer's Disease.

The pathogenesis of Alzheimer's disease (AD), a degenerative disease of the central nervous system, remains unclear. The main manifestations of AD include cognitive and behavioral disorders, neuropsychiatric symptoms, neuroinflammation, amyloid plaques, and neurofibrillary tangles. However, current drugs for AD once the dementia stage has been reached only treat symptoms and do not delay progression, and the research and development of targeted drugs for AD have reached a bottleneck. Thus, other treatment options are needed. Bioactive ingredients derived from plants are promising therapeutic agents. Specifically, Ginkgo biloba (Gb) extracts exert anti-oxidant, anticancer, neuroplastic, neurotransmitter-modulating, blood fluidity, and anti-inflammatory effects, offering alternative options in the treatment of cardiovascular, metabolic, and neurodegenerative diseases. The main chemical components of Gb include flavonoids, terpene lactones, proanthocyanidins, organic acids, polysaccharides, and amino acids. Gb and its extracts have shown remarkable therapeutic effects on various neurodegenerative diseases, including AD, with few adverse reactions. Thus, high-quality Gb extracts are a well-established treatment option for AD. In this review, we summarize the insights derived from traditional Chinese medicine, experimental models, and emerging clinical trials on the role of Gb and its chemical components in the treatment of the main clinical manifestations of AD.

Research on the pathogenesis of Alzheimer's disease based on thalamocortical computational model

Alpha rhythm slowing is an important electroencephalogram(EEG) feature associated with (AD). This study aims to understand the correlation between alpha band deceleration and molecular changes from the perspective of neural computing. Considering the effect of Aβ amyloid deposition on the inhibitory changes in the thalamic, a thalamic cortical model coupled with Aβ amyloid is established. The results show that Aβ amyloid deposition may induce neurotoxicity in thalamic reticular nucleus neurons, which results in inhibitory changes in the thalamus and slows the alpha rhythm of EEG output from the thalamus. In order to understand the pathogenesis more intuitively, some numerical simulations are provided to illustrate the obtained theories. This research is helpful to understand the pathogenesis of AD, so as to provide theoretical basis for the intervention and control of the disease.

Simple modeling of familial Alzheimer’s disease using human pluripotent stem cell-derived cerebral organoid technology

BackgroundCerebral organoids (COs) are the most advanced in vitro models that resemble the human brain. The use of COs as a model for Alzheimer’s disease (AD), as well as other brain diseases, has recently gained attention. This study aimed to develop a human AD CO model using normal human pluripotent stem cells (hPSCs) that recapitulates the pathological phenotypes of AD and to determine the usefulness of this model for drug screening.MethodsWe established AD hPSC lines from normal hPSCs by introducing genes that harbor familial AD mutations, and the COs were generated using these hPSC lines. The pathological features of AD, including extensive amyloid-β (Aβ) accumulation, tauopathy, and neurodegeneration, were analyzed using enzyme-linked immunosorbent assay, Amylo-Glo staining, thioflavin-S staining, immunohistochemistry, Bielschowsky’s staining, and western blot analysis.ResultsThe AD COs exhibited extensive Aβ accumulation. The levels of paired helical filament tau and neurofibrillary tangle-like silver deposits were highly increased in the AD COs. The number of cells immunoreactive for cleaved caspase-3 was significantly increased in the AD COs. In addition, treatment of AD COs with BACE1 inhibitor IV, a β-secretase inhibitor, and compound E, a γ-secretase inhibitor, significantly attenuated the AD pathological features.ConclusionOur model effectively recapitulates AD pathology. Hence, it is a valuable platform for understanding the mechanisms underlying AD pathogenesis and can be used to test the efficacy of anti-AD drugs.

Modulation of Gut Microbiota Through Dietary Intervention in Neuroinflammation and Alzheimer's and Parkinson's Diseases.

The gut microbiota plays a crucial role in the pathogenesis of neuroinflammation and Alzheimer's and Parkinson's diseases. One of the main modulators of the gut microbiota is the diet, which directly influences host homeostasis and biological processes. Some dietary patterns can affect neurodegenerative diseases' progression through gut microbiota composition, gut permeability, and the synthesis and secretion of microbial-derived neurotrophic factors and neurotransmitters. This comprehensive review critically assesses existing studies investigating the impact of dietary interventions on the modulation of the microbiota in relation to neurodegenerative diseases and neuroinflammation. There are limited studies on the effects of specific diets, such as the ketogenic diet, Mediterranean diet, vegetarian diet, and Western diet, on the progression of neuroinflammation and Alzheimer's and Parkinson's diseases through the gut-brain axis. The ketogenic diet displays promising potential in ameliorating the clinical trajectory of mild cognitive impairment and Alzheimer's disease. However, conflicting outcomes were observed among various studies, highlighting the need to consider diverse types of ketogenic diets and their respective effects on clinical outcomes and gut microbiota composition. Vegetarian and Mediterranean diets, known for their anti-inflammatory properties, can be effective against Parkinson's disease, which is related to inflammation in the gut environment. On the other hand, the westernization of dietary patterns was associated with reduced gut microbial diversity and metabolites, which ultimately contributed to the development of neuroinflammation and cognitive impairment. Various studies examining the impact of dietary interventions on the gut-brain axis with regard to neuroinflammation and Alzheimer's and Parkinson's diseases are thoroughly reviewed in this article. A strong mechanistic explanation is required to fully understand the complex interactions between various dietary patterns, gut microbiota, and microbial metabolites and the effects these interactions have on cognitive function and the progression of these diseases.

Machine Learning-Based Perivascular Space Volumetry in Alzheimer Disease.

Impaired perivascular clearance has been suggested as a contributing factor to the pathogenesis of Alzheimer disease (AD). However, it remains unresolved when the anatomy of the perivascular space (PVS) is altered during AD progression. Therefore, this study investigates the association between PVS volume and AD progression in cognitively unimpaired (CU) individuals, both with and without subjective cognitive decline (SCD), and in those clinically diagnosed with mild cognitive impairment (MCI) or mild AD. A convolutional neural network was trained using manually corrected, filter-based segmentations (n = 1000) to automatically segment the PVS in the centrum semiovale from interpolated, coronal T2-weighted magnetic resonance imaging scans (n = 894). These scans were sourced from the national German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study. Convolutional neural network-based segmentations and those performed by a human rater were compared in terms of segmentation volume, identified PVS clusters, as well as Dice score. The comparison revealed good segmentation quality (Pearson correlation coefficient r = 0.70 with P < 0.0001 for PVS volume, detection rate in cluster analysis = 84.3%, and Dice score = 59.0%). Subsequent multivariate linear regression analysis, adjusted for participants' age, was performed to correlate PVS volume with clinical diagnoses, disease progression, cerebrospinal fluid biomarkers, lifestyle factors, and cognitive function. Cognitive function was assessed using the Mini-Mental State Examination, the Comprehensive Neuropsychological Test Battery, and the Cognitive Subscale of the 13-Item Alzheimer's Disease Assessment Scale. Multivariate analysis, adjusted for age, revealed that participants with AD and MCI, but not those with SCD, had significantly higher PVS volumes compared with CU participants without SCD (P = 0.001 for each group). Furthermore, CU participants who developed incident MCI within 4.5 years after the baseline assessment showed significantly higher PVS volumes at baseline compared with those who did not progress to MCI (P = 0.03). Cognitive function was negatively correlated with PVS volume across all participant groups (P ≤ 0.005 for each). No significant correlation was found between PVS volume and any of the following parameters: cerebrospinal fluid biomarkers, sleep quality, body mass index, nicotine consumption, or alcohol abuse. The very early changes of PVS volume may suggest that alterations in PVS function are involved in the pathophysiology of AD. Overall, the volumetric assessment of centrum semiovale PVS represents a very early imaging biomarker for AD.

Biomimetic Nanovesicles as a Dual Gene Delivery System for the Synergistic Gene Therapy of Alzheimer's Disease.

The association between dysfunctional microglia and amyloid-β (Aβ) is a fundamental pathological event and increases the speed of Alzheimer's disease (AD). Additionally, the pathogenesis of AD is intricate and a single drug may not be enough to achieve a satisfactory therapeutic outcome. Herein, we reported a facile and effective gene therapy strategy for the modulation of microglia function and intervention of Aβ anabolism by ROS-responsive biomimetic exosome-liposome hybrid nanovesicles (designated as TSEL). The biomimetic nanovesicles codelivery β-site amyloid precursor protein cleaving enzyme-1 (BACE1) siRNA (siBACE1) and TREM2 plasmid (pTREM2) gene drug efficiently penetrate the blood-brain barrier and enhance the drug accumulation at AD lesions with the help of exosomes homing ability and angiopep-2 peptides. Specifically, an upregulation of TREM2 expression can reprogram microglia from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype while also restoring its capacity to phagocytose Aβ and its nerve repair function. In addition, siRNA reduces the production of Aβ plaques at the source by knocking out the BACE1 gene, which is expected to further enhance the therapeutic effect of AD. The in vivo study suggests that TSEL through the synergistic effect of two gene drugs can ameliorate APP/PS1 mice cognitive impairment by regulating the activated microglial phenotype, reducing the accumulation of Aβ, and preventing the retriggering of neuroinflammation. This strategy employs biomimetic nanovesicles for the delivery of dual nucleic acids, achieving synergistic gene therapy for AD, thus offering more options for the treatment of AD.

Linking Disulfide Levels and NAD+ Metabolism with Alzheimer's Disease for Diagnostic Modeling and Target Drug Analysis.

Alzheimer's disease (AD) is a condition that affects the nervous system and that requires considerably more in-depth study. Abnormal Nicotinamide Adenine Dinucleotide (NAD+) metabolism and disulfide levels have been demonstrated in AD. This study investigated novel hub genes for disulfide levels and NAD+ metabolism in relation to the diagnosis and therapy of AD. Data from the gene expression omnibus (GEO) database were analyzed. Hub genes related to disulfide levels, NAD+ metabolism, and AD were identified from overlapping genes for differentially expressed genes (DEGs), genes in the NAD+ metabolism or disulfide gene sets, and module genes obtained by weighted gene co-expression network analysis (WGCNA). Pathway analysis of these hub genes was performed by Gene Set Enrichment Analysis (GSEA). A diagnostic model for AD was constructed based on the expression level of hub genes in brain samples. CIBERSORT was used to evaluate immune cell infiltration and immune factors correlating with hub gene expression. The DrugBank database was also used to identify drugs that target the hub genes. We identified 3 hub genes related to disulfide levels in AD and 9 related to NAD+ metabolism in AD. Pathway analysis indicated these 12 genes were correlated with AD. Stepwise regression analysis revealed the area under the curve (AUC) for the predictive model based on the expression of these 12 hub genes in brain tissue was 0.935, indicating good diagnostic performance. Additionally, analysis of immune cell infiltration showed the hub genes played an important role in AD immunity. Finally, 33 drugs targeting 10 hub genes were identified using the DrugBank database. Some of these have been clinically approved and may be useful for AD therapy. Hub genes related to disulfide levels and NAD+ metabolism are promising biomarkers for the diagnosis of AD. These genes may contribute to a better understanding of the pathogenesis of AD, as well as to improved drug therapy.

Epigenetic Changes in Alzheimer’s Disease: DNA Methylation and Histone Modification

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive decline and memory loss, imposing a significant burden on affected individuals and their families. Despite the recent promising progress in therapeutic approaches, more needs to be done to understand the intricate molecular mechanisms underlying the development and progression of AD. Growing evidence points to epigenetic changes as playing a pivotal role in the pathogenesis of the disease. The dynamic interplay between genetic and environmental factors influences the epigenetic landscape in AD, altering gene expression patterns associated with key pathological events associated with disease pathogenesis. To this end, epigenetic alterations not only impact the expression of genes implicated in AD pathogenesis but also contribute to the dysregulation of crucial cellular processes, including synaptic plasticity, neuroinflammation, and oxidative stress. Understanding the complex epigenetic mechanisms in AD provides new avenues for therapeutic interventions. This review comprehensively examines the role of DNA methylation and histone modifications in the context of AD. It aims to contribute to a deeper understanding of AD pathogenesis and facilitate the development of targeted therapeutic strategies.