CUERVO, ANA MARIA
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
Understanding Alzheimers Disease in the Context of the Aging Brain
Alzheimer's disease & other dementias
Acquired Cognitive Impairment... Aging... Alzheimer's Disease... Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)... Brain Disorders... Dementia... Neurodegenerative... Neurosciences
Abstract This proposal investigates the role and impact of defective maintenance of protein homeostasis (proteostasis) of the aging brain, in the development and progression of Alzheimers disease. Disturbances in the systems that maintain neuronal proteostasis have been observed in Alzheimers disease, but the extent to which loss of proteostasis in the aging brain constitutes a risk factor for development of Alzheimers disease remains unknown. We will focus in chaperone-mediated autophagy (CMA), a protein quality control system that mediates selective degradation of cytosolic proteins in lysosomes. We have previously found that CMA activity decreases with age and that restoring CMA activity in old mice livers prevents their degeneration and preserves organ function. We propose that 1) the physiological decline of CMA with age increases the susceptibility of the aging brain to Alzheimers disease-related pathology and that 2) interventions to restore normal CMA activity in the aging brain will prevent or slow down progression of Alzheimers disease neurodegeneration. To test this hypothesis we intend to: 1) determine the spatiotemporal sequence of CMA changes in the aging brain to identify areas of higher susceptibility to proteotoxicity and points of no return to proteostasis; 2) investigate if characteristics of the Alzheimers disease brain are phenocopied by neuronal CMA blockage; 3) test if genetic or chemical enhancement of CMA in the aging brain increases its resistance to AD-relevant proteotoxicity and improves neuronal homeostasis and function. Significance: This study will elucidate how functional decline of CMA contributes to brain aging and if it increases Alzheimers disease risk in the aging brain. Our findings could help in developing new approaches to preserve old brain homeostasis and function and reduce its risk to Alzheimers disease neuropathology.
Project Narrative Loss of brain function with age results in part from a failure of the systems responsible for the maintenance of neuronal quality control. We propose that malfunctioning of these surveillance systems is also behind the higher risk of the aging brain for neurodegenerative conditions such as Alzheimers disease. This proposal focuses on one of the mechanisms that contributes to neuronal cleaning, which we have found to malfunction in aging and in brains from Alzheimers patients. We will investigate if failure of this system predisposes to Alzheimers disease neuropathology, and have designed experiments to test the possible therapeutic value of enhancing the activity of this quality control system in the Alzheimers disease brain.