Respiratory chain deficiency alters cellular proteostasis and triggers Alzheimer’s disease-like tau alterations
type: CreativeWork
description: Sporadic Alzheimer’s disease (AD) is defined clinically as a progressive brain disorder resulting in memory loss and, eventually, an inability to perform simple tasks. Pathologically, AD brains accumulate insoluble protein aggregates known as neurofibrillary tangles (NFTs) and amyloid plaques. Definitive diagnosis of AD requires the presence of NFTs and amyloid plaques. Furthermore, variants in genes coding for amyloid associate with early onset forms of the disease. For these reasons and more, removing amyloid plaques from sporadic AD patient brains has been the field’s major therapeutic target for decades. Unfortunately, clinical trials focused on treating AD through amyloid reduction continue to fail. The current standard of care for AD typically extends patient lifespan for months rather than years. The field needs new therapeutic targets and rescuing brain energy production represents a reasonable strategy. Reduced glucose utilization occurs early in AD brains and correlates fairly well with disease progression. Widespread mitochondrial dysfunction accompanies decreased glucose consumption. AD mitochondria display changes in number, ultrastructure, and enzyme activity. The evidence for mitochondrial dysfunction in AD is clear, however, the notion that defective mitochondria could initiate pathological cascades remains controversial. Thus, therapies aimed at mitochondrial function have been slow to reach clinical trials. The following studies examine the relationship between mitochondrial defects and AD pathology and provide evidence that mitochondrial dysfunction leads to AD-relevant retrograde responses. Retrograde responses maintain cellular homeostasis by adapting nuclear gene expression and cytosolic signaling pathways to changes in mitochondrial function. AD mitochondrial dysfunction likely initiates numerous retrograde responses, yet few studies examine defective mitochondria’s influence on AD pathology. Here, we provide evidence that reduced mitochondria…
abstract: Sporadic Alzheimer’s disease (AD) is defined clinically as a progressive brain disorder resulting in memory loss and, eventually, an inability to perform simple tasks. Pathologically, AD brains accumulate insoluble protein aggregates known as neurofibrillary tangles (NFTs) and amyloid plaques. Definitive diagnosis of AD requires the presence of NFTs and amyloid plaques. Furthermore, variants in genes coding for amyloid associate with early onset forms of the disease. For these reasons and more, removing amyloid plaques from sporadic AD patient brains has been the field’s major therapeutic target for decades. Unfortunately, clinical trials focused on treating AD through amyloid reduction continue to fail. The current standard of care for AD typically extends patient lifespan for months rather than years. The field needs new therapeutic targets and rescuing brain energy production represents a reasonable strategy. Reduced glucose utilization occurs early in AD brains and correlates fairly well with disease progression. Widespread mitochondrial dysfunction accompanies decreased glucose consumption. AD mitochondria display changes in number, ultrastructure, and enzyme activity. The evidence for mitochondrial dysfunction in AD is clear, however, the notion that defective mitochondria could initiate pathological cascades remains controversial. Thus, therapies aimed at mitochondrial function have been slow to reach clinical trials. The following studies examine the relationship between mitochondrial defects and AD pathology and provide evidence that mitochondrial dysfunction leads to AD-relevant retrograde responses. Retrograde responses maintain cellular homeostasis by adapting nuclear gene expression and cytosolic signaling pathways to changes in mitochondrial function. AD mitochondrial dysfunction likely initiates numerous retrograde responses, yet few studies examine defective mitochondria’s influence on AD pathology. Here, we provide evidence that reduced mitochondria…
author: Weidling, Ian
language: en
keywords: Biology, Aging, Alzheimer's disease, ApoE, Metabolism, Mitochondria, Proteostasis, Tau
date published: 2019-12-31
date modified: 2026-07-24T02:45:42Z
provider: University of Kansas
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Kansas

PropertyValue
property ID: Handle
value: http://hdl.handle.net/1808/30170