| dc.description.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 mitochondrial respiratory flux leads to AD-like tau alterations, including changes in splicing, conformation and oligomerization. Alzheimer’s disease cybrids recapitulate disease relevant tau alterations. Further experiments suggest mitochondrial function affects cellular proteostasis pathways including the mitochondrial unfolded protein response (mtUPR), integrated stress response (ISR), autophagy/mitophagy, and proteasome function. Although initial studies in C. elegans and rat hepatoma cells established a link between mtDNA depletion and mtUPR activation, we find mammalian cells downregulate the mtUPR upon mtDNA depletion. Instead, mtDNA depleted human cells activate the ISR, a pathway which alters cellular metabolism and halts general protein translation to preserve proteostasis during stress. Finally, we examine how mtDNA depletion affects cytochrome oxidase (COX) and complex I activity. AD tissue displays decreased COX activity, while complex I activity does not change. The reason for specific reductions in COX activity remain unclear. We found COX activity decreases proportionally to declines in mtDNA levels. Whether complex I activity follows the same pattern will give insight into potential mechanisms for reduced COX activity in AD. | |
