Neurometabolic alterations after traumatic brain injury

Rishi Raj Agrawal

Neurodegenerative diseases are highly multifaceted. Despite their heavy burden, treatment options are limited and our understanding of their molecular triggers even less so. In this thesis, I focus on the pathogenesis of Alzheimer’s Disease (AD) due to familial, sporadic and environmental causes. Previous research shows that early AD stages are characterized by upregulated functionality of mitochondria-associated endoplasmic reticulum (ER) membranes. These “MAM” domains of the ER are dynamic contacts between the ER and mitochondria distinguished by a unique lipid composition equivalent to a lipid raft. These sites cluster a specific set of metabolic enzymes that regulate cellular lipid uptake, trafficking and turnover. We find that cleavage of the amyloid precursor protein at MAM domains is intimately involved in MAM regulation through localization of its C-terminal fragment of 99...