Genes and pathways underlying regional and cell type changes in Alzheimer's disease

Miller, Jeremy A.; Woltjer, Randall L.; Goodenbour, Jeff M; Horvath, Steve; Geschwind, Daniel H.

doi:10.1186/gm452

Cited by 236 publications

(217 citation statements)

References 66 publications

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“…AD is associated with widespread transcriptional changes (27,28,(35)(36)(37)(38), which can be rationalized in part by the presence Significance Alzheimer's disease is a neurodegenerative disorder whose molecular origins have been associated with the dysregulation of a set of metastable proteins prone to aggregation. Under conditions of cellular and organismal health, the protein homeostasis system prevents effectively the misfolding and aggregation of these metastable proteins.…”

Section: Resultsmentioning

confidence: 99%

Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

Kundra

Ciryam

Morimoto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Alzheimer's disease is the most common cause of dementia. A hallmark of this disease is the presence of aberrant deposits containing by the Aβ peptide (amyloid plaques) and the tau protein (neurofibrillary tangles) in the brains of affected individuals. Increasing evidence suggests that the formation of these deposits is closely associated with the age-related dysregulation of a large set of highly expressed and aggregation-prone proteins, which make up a metastable subproteome. To understand in more detail the origins of such dysregulation, we identify specific components of the protein homeostasis system associated with these metastable proteins by using a gene coexpression analysis. Our results reveal the particular importance of the protein trafficking and clearance mechanisms, including specific branches of the endosomal-lysosomal and ubiquitin-proteasome systems, in maintaining the homeostasis of the metastable subproteome associated with Alzheimer's disease.Alzheimer's disease | protein aggregation | protein homeostasis | supersaturation

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Section: Resultsmentioning

confidence: 99%

Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

Kundra

Ciryam

Morimoto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…the transcriptional response associated with its onset and progression (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). These studies have revealed that this transcriptional response involves genes corresponding to proteins that can cause the disease and those associated with the cellular processes engaged in combating it (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

“…These studies have revealed that this transcriptional response involves genes corresponding to proteins that can cause the disease and those associated with the cellular processes engaged in combating it (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

A transcriptional signature of Alzheimer’s disease is associated with a metastable subproteome at risk for aggregation

Ciryam

Kundra

Freer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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It is well-established that widespread transcriptional changes accompany the onset and progression of Alzheimer’s disease. Because of the multifactorial nature of this neurodegenerative disorder and its complex relationship with aging, however, it remains unclear whether such changes are the result of nonspecific dysregulation and multisystem failure or instead are part of a coordinated response to cellular dysfunction. To address this problem in a systematic manner, we performed a meta-analysis of about 1,600 microarrays from human central nervous system tissues to identify transcriptional changes upon aging and as a result of Alzheimer’s disease. Our strategy to discover a transcriptional signature of Alzheimer’s disease revealed a set of down-regulated genes that encode proteins metastable to aggregation. Using this approach, we identified a small number of biochemical pathways, notably oxidative phosphorylation, enriched in proteins vulnerable to aggregation in control brains and encoded by genes down-regulated in Alzheimer’s disease. These results suggest that the down-regulation of a metastable subproteome may help mitigate aberrant protein aggregation when protein homeostasis becomes compromised in Alzheimer’s disease.

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“…To ensure that genes found significantly differentially expressed post-landing were not solely a consequence of increased proportion of NK cells, we used a multivariate linear model to regress individual gene expression levels against NK-cell specific marker genes. The criteria for classification as a NK-cell marker were that the genes must be these particular genes needed to be: 1) identified in multiple publications linking them to the NK-cell type; and 2) found intersecting across three independent cell type specific expression databases [CTen (Shoemaker et (Miller et al, 2013), we note that the model is fairly robust to choice of marker genes for cell type.…”

Section: Differential Gene Expression Analysismentioning

confidence: 99%

Acute psychological stress induces short-term variable immune response

Breen

Beliakova-Bethell

Mujica‐Parodi

et al. 2016

Brain, Behavior, and Immunity

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Please cite this article as: Breen, M.S., Beliakova-Bethell, N., Mujica-Parodi, L.R., Carlson, J.M., Ensign, W.Y., Woelk, C.H., Rana, B.K., Acute psychological stress induces short-term variable immune response, Brain, Behavior, and Immunity (2015), doi: http://dx.doi.org/10.1016/j.bbi. 2015.10.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractIn spite of advances in understanding the cross-talk between the peripheral immune system and the brain, the molecular mechanisms underlying the rapid adaptation of the immune system to an acute psychological stressor remain largely unknown.Conventional approaches to classify molecular factors mediating these responses have targeted relatively few biological measurements or explored cross-sectional study designs, and therefore have restricted characterization of stress-immune interactions.This exploratory study analyzed transcriptional profiles and flow cytometric data of peripheral blood leukocytes with physiological (endocrine, autonomic) measurements collected throughout the sequence of events leading up to, during, and after short-term exposure to physical danger in humans. Immediate immunomodulation to acute psychological stress was defined as a short-term selective up-regulation of Natural Killer (NK) cell-associated cytotoxic and IL-12 mediated signaling genes that correlated with increased cortisol, catecholamines and NK cells into the periphery. In parallel, we observed down-regulation of innate immune toll-like receptor genes and genes of the MyD88-dependent signaling pathway. Focusing analyses on discrete groups of coordinately expressed genes (modules) throughout the time-series revealed immune stress responses in modules associated to immune/defense response, response to wounding, cytokine production, TCR signaling and NK cell cytotoxicity which differed between males and females. These results offer a spring-board for future research towards improved treatment of stress-related disease including the impact of stress on cardiovascular and autoimmune disorders, and identifies an immune mechanism by which vulnerabilities to these diseases may be gender-specific.͵

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Genes and pathways underlying regional and cell type changes in Alzheimer's disease

Cited by 236 publications

References 66 publications

Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

A transcriptional signature of Alzheimer’s disease is associated with a metastable subproteome at risk for aggregation

Acute psychological stress induces short-term variable immune response

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