TY - JOUR

T1 - Transcriptomic and epigenomic landscapes of Alzheimer's disease evidence mitochondrial-related pathways

AU - Marmolejo-Garza, Alejandro

AU - Medeiros-Furquim, Tiago

AU - Rao, Ramya

AU - Eggen, Bart J.L.

AU - Boddeke, Erik

AU - Dolga, Amalia M.

N1 - Publisher Copyright: © 2022

PY - 2022

Y1 - 2022

N2 - Alzheimers disease (AD) is the main cause of dementia and it is defined by cognitive decline coupled to extracellular deposit of amyloid-beta protein and intracellular hyperphosphorylation of tau protein. Historically, efforts to target such hallmarks have failed in numerous clinical trials. In addition to these hallmark-targeted approaches, several clinical trials focus on other AD pathological processes, such as inflammation, mitochondrial dysfunction, and oxidative stress. Mitochondria and mitochondrial-related mechanisms have become an attractive target for disease-modifying strategies, as mitochondrial dysfunction prior to clinical onset has been widely described in AD patients and AD animal models. Mitochondrial function relies on both the nuclear and mitochondrial genome. Findings from omics technologies have shed light on AD pathophysiology at different levels (e.g., epigenome, transcriptome and proteome). Most of these studies have focused on the nuclear-encoded components. The first part of this review provides an updated overview of the mechanisms that regulate mitochondrial gene expression and function. The second part of this review focuses on evidence of mitochondrial dysfunction in AD. We have focused on published findings and datasets that study AD. We analyzed published data and provide examples for mitochondrial-related pathways. These pathways are strikingly dysregulated in AD neurons and glia in sex-, cell- and disease stage-specific manners. Analysis of mitochondrial omics data highlights the involvement of mitochondria in AD, providing a rationale for further disease modeling and drug targeting.

AB - Alzheimers disease (AD) is the main cause of dementia and it is defined by cognitive decline coupled to extracellular deposit of amyloid-beta protein and intracellular hyperphosphorylation of tau protein. Historically, efforts to target such hallmarks have failed in numerous clinical trials. In addition to these hallmark-targeted approaches, several clinical trials focus on other AD pathological processes, such as inflammation, mitochondrial dysfunction, and oxidative stress. Mitochondria and mitochondrial-related mechanisms have become an attractive target for disease-modifying strategies, as mitochondrial dysfunction prior to clinical onset has been widely described in AD patients and AD animal models. Mitochondrial function relies on both the nuclear and mitochondrial genome. Findings from omics technologies have shed light on AD pathophysiology at different levels (e.g., epigenome, transcriptome and proteome). Most of these studies have focused on the nuclear-encoded components. The first part of this review provides an updated overview of the mechanisms that regulate mitochondrial gene expression and function. The second part of this review focuses on evidence of mitochondrial dysfunction in AD. We have focused on published findings and datasets that study AD. We analyzed published data and provide examples for mitochondrial-related pathways. These pathways are strikingly dysregulated in AD neurons and glia in sex-, cell- and disease stage-specific manners. Analysis of mitochondrial omics data highlights the involvement of mitochondria in AD, providing a rationale for further disease modeling and drug targeting.

KW - ATAC-seq

KW - Mitochondria

KW - Neurodegeneration

KW - Omics

KW - RNA-seq

U2 - 10.1016/j.bbamcr.2022.119326

DO - 10.1016/j.bbamcr.2022.119326

M3 - Review

C2 - 35839870

AN - SCOPUS:85134419024

VL - 1869

JO - B B A - Molecular Cell Research

JF - B B A - Molecular Cell Research

SN - 0167-4889

IS - 10

M1 - 119326

ER -