Multiscale proteomic modeling reveals protein networks driving Alzheimer's disease pathogenesis.

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.

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 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.

Despite strong evidence supporting that both astrocytes and apolipoprotein E (APOE) play crucial roles in the pathogenesis and progression of Alzheimer's disease (AD), the impact of astrocytes carrying different APOE variants on key AD pathological hallmarks remains largely unknown. To explore such effects in a human relevant context, we generated a chimeric model of AD. We transplanted isogenic APOE3 or APOE4 human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains of AD model mice. We show that at five to six months after transplantation, transplanted cells have differentiated into mature astrocytes (h-astrocytes) that often integrate in upper layers of one cortical hemisphere. APOE3 and APOE4 h-astrocytes differentially express and secrete the APOE protein, which binds to Aβ plaques with an isoform-dependent affinity. Remarkably, APOE3 h-astrocytes ameliorate Aβ pathology, Tau pathology and neuritic dystrophy. In contrast, APOE4 h-astrocytes aggravate these AD processes. Moreover, APOE3 and APOE4 h-astrocytes modulate microglia responses to Aβ pathology in opposite ways. APOE4 h-astrocytes enhance microglia clustering around Aβ plaques and exacerbate DAM state whereas APOE3 h-astrocytes reduce microglia clustering and induce a more homeostatic state on plaque-associated microglia. These findings highlight a critical contribution of h-astrocytes not only to Aβ pathology but also to other key AD hallmarks in chimeric mice. In addition, our findings reveal that h-astrocytes with different APOE variants and the different forms of APOE they secrete have a crucial role in AD progression.

SummaryInduced pluripotent stem cells (iPSCs) are valuable in disease modeling because of their potential to expand and differentiate into virtually any cell type and recapitulate key aspects of human biology. Functional genomics are genome-wide studies that aim to discover genotype-phenotype relationships, thereby revealing the impact of human genetic diversity on normal and pathophysiology. In this review, we make the case that human iPSCs (hiPSCs) are a powerful tool for functional genomics, since they provide an in vitro platform for the study of population genetics. We describe cutting-edge tools and strategies now available to researchers, including multi-omics technologies, advances in hiPSC culture techniques, and innovations in drug development. Functional genomics approaches based on hiPSCs hold great promise for advancing drug discovery, disease etiology, and the impact of genetic variation on human biology.

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

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.

While the accumulation and aggregation of amyloid-β and tau are central events in the pathogenesis of Alzheimer's disease, there is increasing evidence that cerebrovascular pathology is also abundant in Alzheimer's disease brains. In brain capillaries, endothelial cells are connected closely with one another through transmembrane tight junction proteins forming the blood-brain barrier. Because the blood-brain barrier tightly regulates the exchange of molecules between brain and blood and maintains brain homeostasis, its impairment is increasingly recognized as a critical factor contributing to Alzheimer's disease pathogenesis. However, the pathological relationship between blood-brain barrier properties and Alzheimer's disease progression in the human brain is not fully understood. In this study, we show that the loss of cortical tight junction proteins is a common event in Alzheimer's disease, and is correlated with synaptic degeneration. By quantifying the amounts of major tight junction proteins, claudin-5 and occludin, in 12 brain regions dissected from post-mortem brains of normal ageing (n = 10), pathological ageing (n = 14) and Alzheimer's disease patients (n = 19), we found that they were selectively decreased in cortical areas in Alzheimer's disease. Cortical tight junction proteins were decreased in association with the Braak neurofibrillary tangle stage. There was also a negative correlation between the amount of tight junction proteins and the amounts of insoluble Alzheimer's disease-related proteins, in particular amyloid-β40, in cortical areas. In addition, the amount of tight junction proteins in these areas correlated positively with those of synaptic markers. Thus, loss of cortical tight junction proteins in Alzheimer's disease is associated with insoluble amyloid-β40 and loss of synaptic markers. Importantly, the positive correlation between claudin-5 and synaptic markers, in particular synaptophysin, was present independent of insoluble amyloid-β40, amyloid-β42 and tau values, suggesting that loss of cortical tight junction proteins and synaptic degeneration is present, at least in part, independent of insoluble Alzheimer's disease-related proteins. Collectively, these results indicate that loss of tight junction proteins occurs predominantly in the neocortex during Alzheimer's disease progression. Further, our findings provide a neuropathological clue as to how endothelial tight junction pathology may contribute to Alzheimer's disease pathogenesis in both synergistic and additive manners to typical amyloid-β and tau pathologies.

Using human induced pluripotent stem cells (hiPSCs) to investigate the mechanisms by which Apolipoprotein E (APOE) contributes to Alzheimer’s disease (AD) risk

The cholinergic hypothesis is one of the main theories that describe the pathogenesis of Alzheimer's disease (AD). Cholinergic neurons degenerate early and are severely damaged in AD. Despite extensive research, the causes of cholinergic neuron damage and the underlying molecular changes remain unclear. This study aimed to explore the characteristics and transcriptomic changes in cholinergic neurons derived from human induced pluripotent stem cells (iPSCs) with APP mutation. Peripheral blood mononuclear cells from patients with AD and healthy individuals were reprogrammed into iPSCs. The iPSCs were differentiated into cholinergic neurons. Cholinergic neurons were stained, neurotoxically tested, and electrophysiologically and transcriptomically analyzed. The iPSCs-derived cholinergic neurons from a patient with AD carrying a mutation in APP displayed enhanced susceptibility to Aβ1-42-induced neurotoxicity, characterized by severe neurotoxic effects, such as cell body coagulation and neurite fragmentation. Cholinergic neurons exhibited electrophysiological impairments and neuronal death after 21 days of culture in the AD group. Transcriptome analysis disclosed 883 differentially expressed genes (DEGs, 420 upregulated and 463 downregulated) participating in several signaling pathways implicated in AD pathogenesis. To assess the reliability of RNA sequencing, the expression of 16 target DEGs was validated using qPCR. Finally, the expression of the 8 core genes in different cell types of brain was analyzed by the AlzData database. In this study, iPSCs-derived cholinergic neurons from AD patients with APP mutations exhibit characteristics reminiscent of neurodegenerative disease. Transcriptome analysis revealed the corresponding DEGs and pathways, providing potential biomarkers and therapeutic targets for advancing AD research.

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

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.

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.

Endo-lysosomal pathway and ubiquitin-proteasome system dysfunction in Alzheimer's disease pathogenesis