Cell type-specific potential pathogenic genes and functional pathways in Alzheimer’s Disease

Abstract Background Alzheimer's disease (AD) is a pervasive age-related and highly heritable neurodegenerative disorder but has no effective therapy. The complex cellular microenvironment in the AD brain impedes our understanding of pathogenesis. Thus, a comprehensive investigation of cell type-specific responses in AD is crucial to provide precise molecular and cellular targets for therapeutic development. Methods Here, we integrated analyzed 4,441 differentially expressed genes (DEGs) that were identified from 263,370 single-cells in cortex samples by single-nucleus RNA sequencing (snRNA-seq) between 42 AD-pathology subjects and 39 normal controls within 3 studies. DEGs were analyzed in microglia, astrocytes, oligodendrocytes, excitatory neurons, inhibitory neurons, and endothelial cells, respectively. In each cell type, we identified both common DEGs which were observed in all 3 studies, and overlapping DEGs which have been seen in at least 2 studies. Firstly, we showed the common DEGs expression and explained the biological functions by comparing with existing literature or multil-omics signaling pathways knowledgebase. We then determined the significant modules and hub genes, and explored the biological processes using the overlapping DEGs. Finally, we identified the common and distinct dysregulated pathways using overall DEGs and overlapping DEGs in a cell type-specific manner. Results Up-regulated LINGO1 has been seen in both oligodendrocytes and excitatory neurons across 3 studies. Interestingly, genes enriched in the mitochondrial module were up-regulated across all cell types, which indicates mitochondrial dysfunction in the AD brain. The estrogen signaling pathway seems to be the most common pathway that is disrupted in AD. Conclusion Together, these analyses provide detailed information of cell type-specific and overall transcriptional changes and pathways underlying the human AD-pathology. These findings may provide important insights for drug development to tackle this disease.

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Sex-stratified single-cell RNA-Seq analysis identifies sex-specific and cell type-specific transcriptional responses in Alzheimer’s disease across two brain regions.

10.21203/rs.3.rs-418653/v1 ◽

2021 ◽

Author(s):

Stella Belonwu ◽

Yaqiao Li ◽

Daniel Bunis ◽

Arjun Rao ◽

Caroline Warly Solsberg ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Single Cell ◽

Entorhinal Cortex ◽

Neurodegenerative Disorder ◽

Brain Regions ◽

Specific Gene ◽

Cell Type ◽

Transcriptional Responses ◽

Cell Type Specific

Abstract Alzheimer’s disease (AD) is a pervasive neurodegenerative disorder that disproportionately affects women. Since neural anatomy and disease pathophysiology differ by sex, investigating sex-specific mechanisms in AD pathophysiology can inform new therapeutic approaches for both sexes. Here, we utilized nearly 74,000 cells from human prefrontal and entorhinal cortex samples from the first two publicly available single-cell RNA sequencing AD datasets to study cell type-specific sex-stratified transcriptomic perturbations in AD. Our examination at the single-cell level revealed that sex-specific gene and pathway differences in AD were most prominently observed in glial cells of the prefrontal cortex. In the entorhinal cortex, we observed the same genes and pathways to be perturbed in opposing directions between sexes in AD relative to healthy state. Our findings contribute to growing evidence of sex differences in AD-related transcriptomic changes, which can fuel the development of therapies that may prove more effective at reversing AD pathophysiology.

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Emerging Promise of Immunotherapy for Alzheimer’s Disease: A New Hope for the Development of Alzheimer’s Vaccine

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200422105156 ◽

2020 ◽

Vol 20 (13) ◽

pp. 1214-1234 ◽

Cited By ~ 4

Author(s):

Md. Tanvir Kabir ◽

Md. Sahab Uddin ◽

Bijo Mathew ◽

Pankoj Kumar Das ◽

Asma Perveen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune Response ◽

Neutralizing Antibodies ◽

Neurodegenerative Disorder ◽

Symptomatic Relief ◽

Aβ Oligomers ◽

Th2 Immune Response ◽

Age Related ◽

Anti Inflammatory

Background: Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the characteristics of this devastating disorder include the progressive and disabling deficits in the cognitive functions including reasoning, attention, judgment, comprehension, memory, and language. Objective: In this article, we have focused on the recent progress that has been achieved in the development of an effective AD vaccine. Summary: Currently, available treatment options of AD are limited to deliver short-term symptomatic relief only. A number of strategies targeting amyloid-beta (Aβ) have been developed in order to treat or prevent AD. In order to exert an effective immune response, an AD vaccine should contain adjuvants that can induce an effective anti-inflammatory T helper 2 (Th2) immune response. AD vaccines should also possess the immunogens which have the capacity to stimulate a protective immune response against various cytotoxic Aβ conformers. The induction of an effective vaccine’s immune response would necessitate the parallel delivery of immunogen to dendritic cells (DCs) and their priming to stimulate a Th2-polarized response. The aforesaid immune response is likely to mediate the generation of neutralizing antibodies against the neurotoxic Aβ oligomers (AβOs) and also anti-inflammatory cytokines, thus preventing the AD-related inflammation. Conclusion: Since there is an age-related decline in the immune functions, therefore vaccines are more likely to prevent AD instead of providing treatment. AD vaccines might be an effective and convenient approach to avoid the treatment-related huge expense.

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Cell Type-Specific Human APP Transgene Expression by Hippocampal Interneurons in the Tg2576 Mouse Model of Alzheimer’s Disease

Frontiers in Neuroscience ◽

10.3389/fnins.2019.00137 ◽

2019 ◽

Vol 13 ◽

Cited By ~ 1

Author(s):

Corinna Höfling ◽

Emira Shehabi ◽

Peer-Hendrik Kuhn ◽

Stefan F. Lichtenthaler ◽

Maike Hartlage-Rübsamen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Transgene Expression ◽

Tg2576 Mouse ◽

Cell Type ◽

Model Of Alzheimer’S Disease ◽

Cell Type Specific

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Relationship between Wine Consumption, Diet and Microbiome Modulation in Alzheimer’s Disease

Nutrients ◽

10.3390/nu12103082 ◽

2020 ◽

Vol 12 (10) ◽

pp. 3082

Author(s):

M. Victoria Moreno-Arribas ◽

Begoña Bartolomé ◽

José L. Peñalvo ◽

Patricia Pérez-Matute ◽

Maria José Motilva

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Microbiota ◽

Neurodegenerative Disorder ◽

Current Knowledge ◽

Intestinal Microbiome ◽

Dietary Polyphenols ◽

Age Related ◽

Wine Polyphenols ◽

The Impact

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder leading to the most common form of dementia in elderly people. Modifiable dietary and lifestyle factors could either accelerate or ameliorate the aging process and the risk of developing AD and other age-related morbidities. Emerging evidence also reports a potential link between oral and gut microbiota alterations and AD. Dietary polyphenols, in particular wine polyphenols, are a major diver of oral and gut microbiota composition and function. Consequently, wine polyphenols health effects, mediated as a function of the individual’s oral and gut microbiome are considered one of the recent greatest challenges in the field of neurodegenerative diseases as a promising strategy to prevent or slow down AD progression. This review highlights current knowledge on the link of oral and intestinal microbiome and the interaction between wine polyphenols and microbiota in the context of AD. Furthermore, the extent to which mechanisms bacteria and polyphenols and its microbial metabolites exert their action on communication pathways between the brain and the microbiota, as well as the impact of the molecular mediators to these interactions on AD patients, are described.

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Repositioning of Immunomodulators: A Ray of Hope for Alzheimer’s Disease?

Frontiers in Neuroscience ◽

10.3389/fnins.2020.614643 ◽

2020 ◽

Vol 14 ◽

Author(s):

Antonio Munafò ◽

Chiara Burgaletto ◽

Giulia Di Benedetto ◽

Marco Di Mauro ◽

Rosaria Di Mauro ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune System ◽

Neurodegenerative Disorder ◽

Drug Repositioning ◽

Amyloid Β ◽

Deep Understanding ◽

Current Status ◽

Age Related ◽

Tnf Α

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder characterized by cognitive decline and by the presence of amyloid β plaques and neurofibrillary tangles in the brain. Despite recent advances in understanding its pathophysiological mechanisms, to date, there are no disease-modifying therapeutic options, to slow or halt the evolution of neurodegenerative processes in AD. Current pharmacological treatments only transiently mitigate the severity of symptoms, with modest or null overall improvement. Emerging evidence supports the concept that AD is affected by the impaired ability of the immune system to restrain the brain’s pathology. Deep understanding of the relationship between the nervous and the immune system may provide a novel arena to develop effective and safe drugs for AD treatment. Considering the crucial role of inflammatory/immune pathways in AD, here we discuss the current status of the immuno-oncological, immunomodulatory and anti-TNF-α drugs which are being used in preclinical studies or in ongoing clinical trials by means of the drug-repositioning approach.

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Clinical course of Alzheimer’s disease

10.1093/med/9780199569854.003.0002 ◽

2011 ◽

Author(s):

Alberto Lleo ◽

Rafael Blesa

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Daily Living ◽

Clinical Course ◽

Neurodegenerative Disorder ◽

Memory Loss ◽

Remote Memory ◽

Initial Symptom ◽

Delayed Recall ◽

Age Related

• Alzheimer’s disease is an age-related neurodegenerative disorder, with onset usually in late life, characterized by cognitive impairment, a variety of behavioural symptoms, and restrictions in the activities of daily living• The initial symptom is episodic memory loss, in particular in delayed recall of visual and/or verbal material. Immediate and remote memory is usually preserved in early stages...

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Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2008762117 ◽

2020 ◽

Vol 117 (41) ◽

pp. 25800-25809 ◽

Cited By ~ 1

Author(s):

Shun-Fat Lau ◽

Han Cao ◽

Amy K. Y. Fu ◽

Nancy Y. Ip

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Endothelial Cells ◽

Transcriptome Analysis ◽

Cell Type ◽

Angiogenic Growth Factors ◽

Cellular Targets ◽

Therapeutic Development ◽

Single Nucleus ◽

Cell Type Specific

Alzheimer’s disease (AD) is the most common form of dementia but has no effective treatment. A comprehensive investigation of cell type-specific responses and cellular heterogeneity in AD is required to provide precise molecular and cellular targets for therapeutic development. Accordingly, we perform single-nucleus transcriptome analysis of 169,496 nuclei from the prefrontal cortical samples of AD patients and normal control (NC) subjects. Differential analysis shows that the cell type-specific transcriptomic changes in AD are associated with the disruption of biological processes including angiogenesis, immune activation, synaptic signaling, and myelination. Subcluster analysis reveals that compared to NC brains, AD brains contain fewer neuroprotective astrocytes and oligodendrocytes. Importantly, our findings show that a subpopulation of angiogenic endothelial cells is induced in the brain in patients with AD. These angiogenic endothelial cells exhibit increased expression of angiogenic growth factors and their receptors (i.e.,EGFL7,FLT1, andVWF) and antigen-presentation machinery (i.e.,B2MandHLA-E). This suggests that these endothelial cells contribute to angiogenesis and immune response in AD pathogenesis. Thus, our comprehensive molecular profiling of brain samples from patients with AD reveals previously unknown molecular changes as well as cellular targets that potentially underlie the functional dysregulation of endothelial cells, astrocytes, and oligodendrocytes in AD, providing important insights for therapeutic development.

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Cell‐type specific selective vulnerability to pathological tau in Alzheimer's disease

Alzheimer s & Dementia ◽

10.1002/alz.043149 ◽

2020 ◽

Vol 16 (S3) ◽

Author(s):

Emir Turkes ◽

Karen E. Duff

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Selective Vulnerability ◽

Cell Type ◽

Cell Type Specific

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Protein Homeostasis Networks and the Use of Yeast to Guide Interventions in Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21218014 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8014

Author(s):

Sudip Dhakal ◽

Ian Macreadie

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Stress Responses ◽

Cell Biology ◽

Neurodegenerative Disorder ◽

The Elderly ◽

Yeast Cells ◽

Yeast Genome ◽

Protein Homeostasis ◽

Age Related

Alzheimer’s Disease (AD) is a progressive multifactorial age-related neurodegenerative disorder that causes the majority of deaths due to dementia in the elderly. Although various risk factors have been found to be associated with AD progression, the cause of the disease is still unresolved. The loss of proteostasis is one of the major causes of AD: it is evident by aggregation of misfolded proteins, lipid homeostasis disruption, accumulation of autophagic vesicles, and oxidative damage during the disease progression. Different models have been developed to study AD, one of which is a yeast model. Yeasts are simple unicellular eukaryotic cells that have provided great insights into human cell biology. Various yeast models, including unmodified and genetically modified yeasts, have been established for studying AD and have provided significant amount of information on AD pathology and potential interventions. The conservation of various human biological processes, including signal transduction, energy metabolism, protein homeostasis, stress responses, oxidative phosphorylation, vesicle trafficking, apoptosis, endocytosis, and ageing, renders yeast a fascinating, powerful model for AD. In addition, the easy manipulation of the yeast genome and availability of methods to evaluate yeast cells rapidly in high throughput technological platforms strengthen the rationale of using yeast as a model. This review focuses on the description of the proteostasis network in yeast and its comparison with the human proteostasis network. It further elaborates on the AD-associated proteostasis failure and applications of the yeast proteostasis network to understand AD pathology and its potential to guide interventions against AD.

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