Speakers - NWC 2024

Abstract

Alzheimer’s disease (AD) is a progressive, incurable neurodegenerative disorder that results in cognitive impairment, behavioral changes, and deterioration in language skills, memory, reasoning, and judgment. It is the most common form of dementia, affecting millions of older persons across the globe, and is ultimately fatal. Huge efforts and resources concentrated on AD treatments based on prevention of accumulation in the brain of misfolded proteins amyloid-β and hyperphosphorylated tau have yielded only marginal success. Our group and others have, therefore, shifted focus to address the disruption of mitochondrial dynamics and function that occur in the preclinical phase early in AD neurodegeneration. AD neuropathology begins approximately 20 years before the appearance of clinical symptoms. Energy demand by the brain is disproportionately high in relation to its small percentage of body weight. It consumes about 20% of the total ATP produced by the body. A progressive decline in the glucose metabolic rate in some regions of the brain is a key feature of AD that promotes synaptic loss. Mitochondrial respiratory chain impairments lead to critical deficits in brain energy homeostasis, to the production of highly damaging reactive oxygen species, and to calcium overload. An imbalance in levels of mitochondrial fusion and fission proteins favors fission, fragmentation, and mitophagy. In addition, dysregulated mitophagy can result in faulty mitochondrial clearance and accumulation of defective brain mitochondria. This presentation will examine technologies advancing the AD field, such as functional imaging, quantitative proteomics, live cell bioenergetics, and bioinformatics/computational biology. We will discuss the mechanisms and consequences of altered energy metabolism in AD. We will provide an overview of cutting-edge therapeutic approaches to stabilizing and correcting energy imbalance in the AD brain in hopes of prolonging neuronal survival and ameliorating neuropathological changes.