Salicin ameliorates Alzheimer's-like pathology by modulation of NTSP/CSP/GLM pathways: An integrated in silico and in vivo approach.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized pathologically by the presence of senile plaques, neurofibrillary tangles, and synapse loss. Increasing evidence supports a role of amyloid beta-peptide (Abeta)-induced oxidative stress in the progression and pathogenesis of AD. In this review, we summarize evidence for a role of oxidative stress in the progression of AD by comparing the appearance of the same oxidized brain proteins from subjects with mild cognitive impairment (MCI), early AD (EAD), and late-stage AD, and relating these findings to the reported AD pathology. The identification of oxidized brain proteins in common in MCI, EAD, and AD brain suggest that certain key pathways are triggered and may be involved in the progression of AD. Exploring these pathways in detail may provide clues for better understanding the pathogenesis and progression of AD and also for the development of effective therapies to treat or delay this dementing disorder.

New unexpected role for Wolfram Syndrome protein WFS1: a novel therapeutic target for Alzheimer's disease?

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

BACKGROUND The etiological tapestry of Alzheimer's disease (AD) is a complex and multifaceted genomic symphony, in which intricate molecular mechanisms orchestrate the pathogenesis of this devastating neurodegenerative disorder. This study embarks on an unprecedented exploration aiming to decode the genomic symphony and unveil the intricate molecular mechanisms underlying AD pathogenesis. The foundational pillars of this research are rooted in cutting-edge genomics technologies, including single-cell sequencing, chromatin conformation capture, and integrative multi-dimensional analyses, employed to dissect the intricate genomic landscape associated with AD. The seminal discovery by Goate et al. [1] associating missense mutations in the amyloid precursor protein gene (APP) with familial AD forms the cornerstone of genetic exploration of AD. This transformative finding laid the groundwork for subsequent investigations into the role of APP and its proteolytic products in the amyloid cascade hypothesis, a pivotal theory in AD pathogenesis [1]. However, as genomic technologies have advanced, our understanding has evolved to encompass a broader spectrum of genetic and epigenetic factors contributing to the intricate symphony of AD pathogenesis. Expanding beyond the confines of coding sequences, recent studies highlight the crucial role of non-coding RNAs in neurodegenerative diseases, including AD [2]. The non-coding genomic landscape, once considered mere genomic "noise," now emerges as a harmonious participant in the intricate regulatory symphony governing gene expression and cellular processes [2]. Systems biology, as a guiding paradigm, has become indispensable in understanding the dynamic interactions within the genomic symphony. The work of Zhang et al. [3] on late-onset AD has exemplified the power of systems biology approaches in identifying genetic nodes and networks, offering a holistic view of the molecular complexities underpinning AD. Moreover, the exploration of three-dimensional genomic architecture through chromatin conformation capture, as exemplified by studies like the one conducted by Javierre et al. [4], promises to unravel spatial genomic dynamics, adding another layer of complexity to the genomic symphony in AD pathogenesis. As we navigate through this intricate genomic symphony, this study aspires to illuminate the nuanced interactions between genetics and epigenetics, coding and non-coding elements, and single-cell heterogeneity in AD pathogenesis. By integrating diverse layers of genomic information, this research seeks to contribute transformative insights that transcend the current understanding of AD, paving the way for innovative therapeutic strategies in the realm of neurodegenerative disorders. The main objective of this review is to synthesize and critically analyze current knowledge on the genomic mechanisms contributing to the pathogenesis of Alzheimer's disease, encompassing genetic variations, epigenetic modifications, non-coding RNA regulation, three-dimensional genomic architecture, and the integration of systems biology approaches. OBJECTIVE The main objective of this review is to synthesize and critically analyze current knowledge on the genomic mechanisms contributing to the pathogenesis of Alzheimer's disease, encompassing genetic variations, epigenetic modifications, non-coding RNA regulation, three-dimensional genomic architecture, and the integration of systems biology approaches. METHODS In order to compile information on Decoding the Genomic Symphony: Unraveling Molecular Mechanisms in Alzheimer's disease Pathogenesis, in-depth assessment of scientific publications and academic research databases was employed for the study, these databases include journal articles, related project materials, and review articles. Therefore, articles were searched using the following keywords: Alzheimer's disease, Pathogenesis, Genomic Symphony and Molecular Mechanisms. Based on the keywords searched, 5, 121 works related Alzheimer's disease, Pathogenesis, Genomic Symphony and Molecular Mechanisms were found in the chosen databases. Furthermore, the selection procedure was carried out based on the title of the paper, abstract and English scholarly databases. Only information on the Alzheimer's disease, Pathogenesis, Genomic Symphony and Molecular Mechanisms were considered which amount to 71 articles. RESULTS Through our comprehensive review, we identified key genomic signatures associated with disease progression. Our findings reveal dysregulated pathways implicated in neuroinflammation, synaptic dysfunction, and mitochondrial dysfunction. Furthermore, we delineate dynamic epigenetic modifications underlying AD pathogenesis, including alterations in DNA methylation patterns and histone modifications. Importantly, we identify novel candidate genes and non-coding RNAs with potential diagnostic and therapeutic relevance. CONCLUSIONS This study provides unprecedented insights into the genomic landscape of AD, unraveling intricate molecular mechanisms underlying disease pathogenesis. Our findings deepen our understanding of the complex interplay between genetic predisposition, environmental factors, and epigenetic modifications in disease onset and progression. Moreover, the identification of novel candidate genes and therapeutic targets opens up avenues for the development of precision medicine approaches tailored to individual patients. Ultimately, our findings have the potential to catalyze the development of effective treatments and diagnostic tools, offering hope to millions of individual affected by AD worldwide CLINICALTRIAL In this odyssey through the genomic symphony of Alzheimer's disease (AD) pathogenesis, our exploration has delved into the intricate molecular harmonies and discordances shaping the neurodegenerative landscape. The synthesis of cutting-edge genomics technologies, encompassing single-cell sequencing, chromatin conformation capture, and multi-dimensional integrative analyses, has provided a panoramic view of the genomic symphony, unraveling the complex molecular mechanisms orchestrating AD progression. Therefore, this study envisions a future where the decoding of the genomic symphony not only deepens our understanding of AD but also paves the way for transformative interventions. As we continue this exploration, let the genomic symphony be a guide, resonating with the hope for innovative strategies that may one day harmonize the discordant notes of Alzheimer's disease into a melody of precision therapeutics.

Extracellular amyloid plaques, intracellular neurofibrillary tangles, and loss of basal forebrain cholinergic neurons in the brains of Alzheimer's disease (AD) patients may be the end result of abnormalities in lipid metabolism and peroxidation that may be caused, or exacerbated, by beta-amyloid peptide (Abeta). Apolipoprotein E (apoE) is a major apolipoprotein in the brain, mediating the transport and clearance of lipids and Abeta. ApoE-dependent dendritic and synaptic regeneration may be less efficient with apoE4, and this may result in, or unmask, age-related neurodegenerative changes. The increased risk of AD associated with apoE4 may be modulated by diet, vascular risk factors, and genetic polymorphisms that affect the function of other transporter proteins and enzymes involved in brain lipid homeostasis. Diet and apoE lipoproteins influence membrane lipid raft composition and the properties of enzymes, transporter proteins, and receptors mediating Abeta production and degradation, tau phosphorylation, glutamate and glucose uptake, and neuronal signal transduction. The level and isoform of apoE may influence whether Abeta is likely to be metabolized or deposited. This review examines the current evidence for diet, lipid homeostasis, and apoE in the pathogenesis of AD. Effects on the cholinergic system and response to cholinesterase inhibitors by APOE allele carrier status are discussed briefly.

Alzheimer's disease (AD) is a common neurodegenerative disease and mild cognitive impairment (MCI) is considered as the prodromal stage of AD. Previous studies showed that changes in the neurotrophin signaling pathway could lead to cognitive decline in AD. However, the association of single nucleotide polymorphisms (SNPs) in genes that are involved in this pathway with AD progression from MCI remains unclear. We investigated the associations between SNPs involved in the neurotrophin signaling pathway with AD progression. We performed single-locus analysis to identify neurotrophin-signaling-related SNPs associated with the AD progression using 767 patients from the Alzheimer's Disease Neuroimaging Initiative study and 1,373 patients from the National Alzheimer's Coordinating Center study. We constructed polygenic risk scores (PRSs) using the identified independent non-APOE SNPs and evaluated its prediction performance on AD progression. We identified 25 SNPs significantly associated with AD progression with Bayesian false-discovery probability ≤0.8. Based on the linkage disequilibrium clumping and expression quantitative trait loci analysis, we found 6 potentially functional SNPs that were associated with AD progression independently. The PRS analysis quantified the combined effects of these SNPs on longitudinal cognitive assessments and biomarkers from cerebrospinal fluid and neuroimaging. The addition of PRSs to the prediction model for 3-year progression to AD from MCI significantly increased the predictive accuracy. Genetic variants in the specific genes of the neurotrophin signaling pathway are predictors of AD progression. eQTL analysis supports that these SNPs regulate expression of key genes involved in the neurotrophin signaling pathway.

Estrogens are pivotal regulators of brain function throughout the lifespan, exerting profound effects from early embryonic development to aging. Extensive experimental evidence underscores the multifaceted protective roles of estrogens on neurons and neurotransmitter systems, particularly in the context of Alzheimer's disease (AD) pathogenesis. Studies have consistently revealed a greater risk of AD development in women compared to men, with postmenopausal women exhibiting heightened susceptibility. This connection between sex factors and long-term estrogen deprivation highlights the significance of estrogen signaling in AD progression. Estrogen's influence extends to key processes implicated in AD, including amyloid precursor protein (APP) processing and neuronal health maintenance mediated by brain-derived neurotrophic factor (BDNF). Reduced BDNF expression, often observed in AD, underscores estrogen's role in preserving neuronal integrity. Notably, hormone replacement therapy (HRT) has emerged as a sex-specific and time-dependent strategy for primary cardiovascular disease (CVD) prevention, offering an excellent risk profile against aging-related disorders like AD. Evidence suggests that HRT may mitigate AD onset and progression in postmenopausal women, further emphasizing the importance of estrogen signaling in AD pathophysiology. This review comprehensively examines the physiological and pathological changes associated with estrogen in AD, elucidating the therapeutic potential of estrogen-based interventions such as HRT. By synthesizing current knowledge, it aims to provide insights into the intricate interplay between estrogen signaling and AD pathogenesis, thereby informing future research directions and therapeutic strategies for this debilitating neurodegenerative disorder.

Alzheimer's disease (AD) is a complex neurodegenerative disorder with major clinical hallmarks of memory loss, dementia, and cognitive impairment. Besides the extensive neuron-oriented research, an increasing body of evidence suggests that glial cells, namely astrocytes, microglia, NG2 glia and oligodendrocytes, may play an important role in the pathogenesis of this disease. In the first part of this review, AD pathophysiology in humans is briefly described and compared with disease progression in routinely used animal models. The relevance of findings obtained in animal models of AD is also discussed with respect to AD pathology in humans. Further, this review summarizes recent findings regarding the role/participation of glial cells in pathogenesis of AD, focusing on changes in their morphology, functions, proteins and gene expression profiles. As for astrocytes and microglia, they are fundamental for the progression and outcome of AD either because they function as effector cells releasing cytokines that play a role in neuroprotection, or because they fail to fulfill their homeostatic functions, ultimately leaving neurons to face excitotoxicity and oxidative stress. Next, we turn our attention towards NG2 glia, a novel and distinct class of glial cells in the central nervous system (CNS), whose role in a variety of human CNS diseases has begun to emerge, and we also consider the participation of oligodendrocytes in the pathogenesis and progression of AD. Since AD is currently an incurable disease, in the last part of our review we hypothesize about possible glia-oriented treatments and provide a perspective of possible future advancements in this field.

Memory loss in Alzheimer's disease: are the alterations in the UPR network involved in the cognitive impairment?

Emerging evidence suggests that peripheral immunoinflammatory responses contribute to Alzheimer's disease (AD) pathogenesis, and endothelial cells (ECs) are involved in these responses. Nevertheless, the potential molecular mechanisms and signaling pathways by which ECs modulate peripheral immunoinflammatory responses and thus contribute to AD pathogenesis are not fully understood. The single-cell RNA sequencing dataset GSE157827 was analyzed, and AD key genes were screened using LASSO regression and random forest algorithms. Functional enrichment analyses of these AD key genes were conducted using gene set enrichment analysis (GSEA) and gene set variation analysis. Immune cell infiltration analyses for AD key genes were performed using single-sample GSEA, and their correlations with immunoinflammatory factors were assessed using the TISIDB database. Peripheral blood RNA sequencing data from our cohort were utilized to validate the expression patterns of EC-related AD key genes in peripheral blood and to investigate their association with cognition. ECs are the most significant contributors to AD among all brain cell subpopulations. For the first time, the EC-related genes EIF1 and HSPA1B were identified as key genes associated with AD progression. These two EC-related key genes may participate in AD pathogenesis by modulating peripheral immunoinflammatory responses. The levels of EIF1 and HSPA1B were significantly altered in the peripheral blood during AD progression, and EIF1 levels correlated with cognitive functions in AD clinical continuum patients. These findings underscore the critical roles of the EC-related genes EIF1 and HSPA1B in AD pathogenesis and their potential as biomarkers for this disease.

Background: Alzheimer's disease (AD) is a neurodegenerative disorder influenced by genetic and environmental factors. APOE, APP, PSEN1, PSEN2, CLU, SORL1, BIN1, CR1, PICALM, TREM2, ABCA7, and CD33 play key roles in AD pathogenesis, affecting biochemical pathways and cellular processes. However, the interaction between genetic predisposition and environmental factors, as well as the reasons for variability in disease phenotype, remain poorly understood. This study aims to investigate these interactions to improve our understanding of AD etiology and inform personalized interventions. Methods: A comprehensive search encompassing databases such as PubMed, MEDLINE, Google Scholar, and open access/subscription-based journals was conducted to retrieve relevant articles for the investigation of genes involved in Alzheimer's disease (AD) pathogenesis, including APOE, APP, PSEN1, PSEN2, CLU, SORL1, BIN1, CR1, PICALM, TREM2, ABCA7, and CD33. Articles were searched without any date restrictions. Utilizing the criteria delineated in the methodology section, studies were systematically reviewed to elucidate how environmental factors and genetics influence Alzheimer's disease onset, progression, symptom severity, and progression rates. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Results: Our investigation revealed the complicated interactions between genetic predisposition, environmental factors, biochemical pathways, and cellular processes in Alzheimer's disease (AD) pathogenesis. APOE, APP, PSEN1, PSEN2, CLU, SORL1, BIN1, CR1, PICALM, TREM2, ABCA7, and CD33 influence amyloid-beta production, tau pathology, lipid metabolism, and inflammation in AD. These genes interact with environmental factors such as diet, pollutants, head trauma, and lifestyle, modulating disease risk and progression. Additionally, we found variability in disease phenotype among individuals carrying similar genetic mutations, influenced by genetic modifiers, environmental factors, cognitive reserve, and neurobiological differences. Conclusion: Alzheimer's disease (AD) is a multifactorial disorder influenced by genetic and environmental factors. APOE, APP, PSEN1, PSEN2, CLU, SORL1, BIN1, CR1, PICALM, TREM2, ABCA7, and CD33 play critical roles in AD pathogenesis by affecting amyloid-beta production, tau pathology, lipid metabolism, and inflammation. These genes interact with environmental factors such as diet, pollutants, head trauma, and lifestyle, further modulating disease risk and progression. Understanding these complicated interactions is essential for developing personalized interventions to delay onset, reduce severity, and slow AD progression.

AMP-activated protein kinase (AMPK) is a cellular energy censor that has been implicated in Alzheimer's disease (AD). The catalytic α isoforms (α1 and α2) of AMPK are normally expressed in a homeostatic equilibrium but are differentially expressed in AD brains, with α2 expression significantly decreased compared to controls. AMPK dysregulation may be an early feature of AD that promotes accelerated cognitive decline through its roles in protein synthesis regulation, metabolism, autophagy, and mitochondrial biogenesis. The early loss of the α2 isoform may exacerbate or accelerate disease progression in the preclinical stage. AMPKα2 was conditionally knocked down in excitatory forebrain neurons in the Tg19959 AD mouse model to create a heterozygous AMPKα2/Tg19959 double mutant. At 3-5 months of age, before cognitive impairments become evident, the mice were subjected to the Morris Water Maze (MWM) and Novel Object Recognition (NOR) task that measures hippocampus-dependent spatial learning and memory. In addition, Golgi staining, immunohistochemistry, and transmission electron microscopy of the hippocampus were performed. The double mutant AMPKα2/Tg19959 mice showed significant memory impairments in both the MWM and NOR task compared to wild type, Tg19959, and α2/Cre littermates. The AMPKα2/Tg19959 double mutant mice also showed significant decreases in post-synaptic density size and in the number of polyribosomes. Differences in spine morphology and amyloid plaque deposition were also observed. AMPKα2 knockdown in a "pre-symptomatic" AD mouse model leads to accelerated cognitive deficits and disruption of protein synthesis regulatory mechanisms. Taken together, these findings suggest that reduction of AMPKα2 may exacerbate or accelerate cognitive decline and AD pathogenesis. This finding could provide a future therapeutic target for the treatment of AD.

The sequence of cellular dysfunctions in preclinical Alzheimer's disease must be understood if we are to plot new therapeutic routes. Hippocampal neuronal hyperactivity is one of the earliest events occurring during the preclinical stages of Alzheimer's disease in both humans and mouse models. The most common hypothesis describes amyloid-β accumulation as the triggering factor of the disease but the effects of this accumulation and the cascade of events leading to cognitive decline remain unclear. In mice, we previously showed that amyloid-β-dependent TRPA1 channel activation triggers hippocampal astrocyte hyperactivity, subsequently inducing hyperactivity in nearby neurons. In this work, we investigated the potential protection against Alzheimer's disease progression provided by early chronic pharmacological inhibition of the TRPA1 channel. A specific inhibitor of TRPA1 channel (HC030031) was administered intraperitoneally from the onset of amyloid-β overproduction in the APP/PS1-21 mouse model of Alzheimer's disease. Short-, medium- and long-term effects of this chronic pharmacological TRPA1 blockade were characterized on Alzheimer's disease progression at functional (astrocytic and neuronal activity), structural, biochemical and behavioural levels. Our results revealed that the first observable disruptions in the Alzheimer's disease transgenic mouse model used correspond to aberrant hippocampal astrocyte and neuron hyperactivity. We showed that chronic TRPA1 blockade normalizes astrocytic activity, avoids perisynaptic astrocytic process withdrawal, prevents neuronal dysfunction and preserves structural synaptic integrity. These protective effects preserved spatial working memory in this Alzheimer's disease mouse model. The toxic effect of amyloid-β on astrocytes triggered by TRPA1 channel activation is pivotal to Alzheimer's disease progression. TRPA1 blockade prevents irreversible neuronal dysfunction, making this channel a potential therapeutic target to promote neuroprotection.

Disclosure: S. Sims: None. F. Sen: None. F. Sultana: None. A. Liu: None. V. Laurencin: None. A. Gumerova: None. O. Barak: None. S. Rojekar: None. A.R. Pallapati: None. L. Cullen: None. R. Chen: None. K. Goosens: None. V. Ryu: None. T. Yuen: None. M. Zaidi: None. T. Frolinger: None. F. Korkmaz: None. Alzheimer’s disease (AD) is a major progressive neurodegenerative disorder of the aging population, accounting for more than 60-80% of dementia cases. High serum level of the pituitary gonadotropin, follicle-stimulating hormone (FSH), is strongly associated with the onset of AD. We recently showed that FSH activates hippocampal Fshr to drive AD–like pathology and cognitive impairment in AD mice, that FSH blockade in these mice abrogates the AD-like phenotype by inhibiting the neuronal C/EBPβ–δ-secretase pathway, and that FSH and ApoE4, the most prevalent genetic risk factor of AD, jointly trigger AD-like pathogenesis by activating C/EBPβ-δ-secretase signaling. To further confirm the role of FSH in AD cognitive decline, we used female 3xTg;Fshr+/+, 3xTg;Fshr+/– and 3xTg;Fshr–/– mice that underwent sham surgery or ovariectomy (OVX) at 8 weeks of age. Sham-operated 3xTg;Fshr–/– mice were implanted with 17β-estradiol pellets to normalize E2 levels. Morris Water Maze (MWM) and Novel object recognition (NOR) tests were perform in these mice to assess spatial and recognition memory, respectively. 3xTg;Fshr+/+ mice displayed impaired spatial memory at 5-month of age in the MWM test. This impairment, in both the learning and retrieval phases, is significantly ameliorated in 3xTg;Fshr–/– mice and to a lesser extent in 3xTg;Fshr+/– mice, suggesting that Fshr expression has a negative impact on memory. At 5 and 10 months of age, sham-operated 3xTg;Fshr–/– mice show better memory performance in the MWM test during the learning phase when compared to their wild-type littermates, suggesting a rescue of spatial memory and progression with age. However, this rescue was not seen when mice were ovariectomized. At 5 months of age, sham-operated 3xTg;Fshr–/– mice displayed better memory retrieval compared with 3xTg;Fshr+/+ mice. This effect was not observed when the mice were 10-month-old, suggesting that the beneficial effect of the absence of FSH signaling on memory consolidation could be masked by disease severity and older age. OVX 3xTg;Fshr+/+, 3xTg;Fshr+/– mice displayed a decline in memory consolidation at 10-months of age compared with 5-month of age, while the 3xTg;Fshr–/– mice showed a significantly slower decline. Using the NOR test, we found impaired recognition memory in 10-month-old sham-operated or OVX 3xTg;Fshr+/+ and 3xTg;Fshr+/– mice; this effect was prevented in OVX 3xTg;Fshr–/– mice. Finally, 3xTg;Fshr–/– mice displayed lower Aβ40 and Aβ42 levels in the brain (ELISA). Altogether, our results confirm a protective effect of absent Fshr signaling on spatial learning, consolidation, memory retrieval, recognition memory and reduction of brain Aβ40 and Aβ42. Presentation: 6/1/2024

GPR55 deficiency exacerbates cognitive impairments and Alzheimer's disease-like pathology in mice.