Microglia in Alzheimer's Disease: Risk Factors and Inflammation

Katsumoto, Atsuko; Takeuchi, Hideyuki; Takahashi, Keita; Tanaka, Fumiaki

doi:10.3389/fneur.2018.00978

Cited by 112 publications

(79 citation statements)

References 82 publications

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“…Many transcriptomic analyses have shown that there are significant upregulation of immune response genes and downregulation of neuronal function genes in AD (Miller et al, 2008;Zhang et al, 2013). It is widely accepted that microglia clusters near amyloid plaques and microgliamediated inflammation are activated in in the progression of AD (Clayton et al, 2017;Hansen et al, 2018;Katsumoto et al, 2018). However, most of such studies used bulk brain samples containing mixed cell types without taking microglia cell abundance change into account.…”

Section: Discussionmentioning

confidence: 99%

Combinatorial analyses reveal that cellular composition changes have different impact on transcriptomic changes of cell type specific genes in Alzheimer’s Disease brains

Xiang

Johnson

Dong

et al. 2020

Preprint

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Background Alzheimer’s disease (AD) brains are characterized by progressive neuron loss and gliosis which involves mostly microglia and astrocytes. Comparative transcriptomic analysis on AD vs. normal brain tissues helps to identify key genes/pathways involved in AD initiation and progression. However, many such studies using bulk brain tissue samples have not considered cell composition changes in AD brains, which may lead to expression changes that are not due to transcriptional regulation. Methods Using five large transcriptomic datasets including 1,681 brain tissue samples (882 AD, 799 normal) in total, we first mined frequent co-expression network modules across them, then combined differential expression and differential co-expression analysis on the mined modules in AD versus normal brains. Integrated with cell type deconvolution analysis, we addressed the question of whether the module expression changes are due to altered cellular composition or transcriptional regulation. We then used four additional large AD/normal transcriptomic datasets to validate our findings. Results The integrative analysis revealed highly elevated expression level of microglia modules in AD without co-expression change. Decreased expression and elevated co-expression are observed for neuron modules in AD, while significant over-expression and co-expression perturbation are observed in astrocyte modules, all of which has not been previously reported. The expression levels of astrocyte modules also show the strongest correlation with the clinicopathological biomarkers among all cell type specific modules. Conclusion Further analysis indicated that the overall increased expression of the core microglia modules can be well explained by the increased microglia cell population in AD brains instead of bona fide microglia genes’ upregulation. In contrast, the decreased expression and perturbed co-expression in AD neuron modules are due to both neuron cell loss and expression regulation of neuronal pathways including differentially expressed transcription factors such as BCL6 and STAT3, which previous study was not able to identify from the shadow of the cellular composition change. Similarly, the strong changes in expression and co-expression in the astrocyte modules may be also due to a combinatory effect from astrogliosis and astrocyte gene activation in AD brains. In this work, we demonstrated that the combinatorial analyses not only provide a powerful approach to delineate the origin of transcriptomic changes in bulk tissue data, but also lead to a deeper understanding of genes in AD.

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Section: Discussionmentioning

confidence: 99%

Combinatorial analyses reveal that cellular composition changes have different impact on transcriptomic changes of cell type specific genes in Alzheimer’s Disease brains

Xiang

Johnson

Dong

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The studies conducted on postmortem brain tissues have revealed excessive chronic inflammation in the plaque area. A key phenomenon underlying AD-related neuroinflammation is the proliferation and accumulation of microglial cells around plaques, which results in the expression of pro-inflammatory cytokines and chemokines as well as neuronal cell death (42)(43)(44).…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Sphingolipids in neuroinflammation: a potential target for diagnosis and therapy

2020

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Sphingolipids are ubiquitous building blocks of eukaryotic cell membranes that function as signaling molecules for regulating a diverse range of cellular processes, including cell proliferation, growth, survival, immune-cell trafficking, vascular and epithelial integrity, and inflammation. Recently, several studies have highlighted the pivotal role of sphingolipids in neuroinflammatory regulation. Sphingolipids have multiple functions, including induction of the expression of various inflammatory mediators and regulation of neuroinflammation by directly effecting the cells of the central nervous system. Accumulating evidence points to sphingolipid engagement in neuroinflammatory disorders, including Alzheimer's and Parkinson's diseases. Abnormal sphingolipid alterations, which involves an increase in ceramide and a decrease in sphingosine kinase, are observed during neuroinflammatory disease. These trends are observed early during disease development, and thus highlight the potential of sphingolipids as a new therapeutic and diagnostic target for neuroinflammatory diseases. [BMB Reports 2020; 53(1): 28-34]

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“…In the case of AD, these microglial cells of the brain assem-ble around the neurons but are not successful in performing their function of clearing the debris. Thus, their build-up results in the release of chemicals that lead to chronic inflammation in the brain [10]. 5.…”

Section: Formation Of A␤ Plaques Formation Of A␤ Pro-mentioning

confidence: 99%

Nature’s Derivative(s) as Alternative Anti-Alzheimer’s Disease Treatments

Sharma

Kumar

2019

ADR

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Alzheimer's disease (AD), the 'Plague of Twenty-First Century,' is a crippling neurodegenerative disease that affects a majority of the older population globally. By 2050, the incidence of AD is expected to rise to 135 million, while no treatment(s) that can reverse or control the progression of AD are currently available. The treatment(s) in use are limited in their ability to manage the symptoms or slow the progression of the disease and can lead to some severe side effects. The overall care is economically burdensome for the affected individuals as well as the caretakers or family members. Thus, there is a pressing need to identify and develop much safer alternative therapies that can better manage AD. This review discusses a multitude of such treatments borrowed from Ayurveda, traditional Chinese practices, meditation, and exercising for AD treatment. These therapies are in practice since ancient times and reported to be beneficial as anti-AD therapies. Ayurvedic drugs like turmeric, Brahmi, Ashwagandha, etc., management of stress by meditation, regular exercising, and acupuncture have been reported to be efficient in their anti-AD usage. Besides, a combination of vitamins and natural dietary intakes is likely to play a significant role in combating AD. We conclude that the use of such alternative strategies will be a stepping-stone in preventing, treating, curing, or managing the disease.

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Microglia in Alzheimer's Disease: Risk Factors and Inflammation

Cited by 112 publications

References 82 publications

Combinatorial analyses reveal that cellular composition changes have different impact on transcriptomic changes of cell type specific genes in Alzheimer’s Disease brains

Combinatorial analyses reveal that cellular composition changes have different impact on transcriptomic changes of cell type specific genes in Alzheimer’s Disease brains

Sphingolipids in neuroinflammation: a potential target for diagnosis and therapy

Nature’s Derivative(s) as Alternative Anti-Alzheimer’s Disease Treatments

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