Title: Neurometabolic alterations after traumatic brain injury
Description: 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 a.a., C99, to MAM regions. C99 upregulates MAM functionality by promoting cholesterol uptake and trafficking to the ER for esterification, observable in both familial and sporadic AD samples.

Here, we recapitulated these phenotypes in a mouse model of an environmental AD trigger: traumatic brain injury (TBI). Through biochemical, transcriptional and lipidomic analyses, we observed MAM functionality to be upregulated following a single brain injury. This was determined by assessment of phospholipid synthesis and cholesterol esterification. This correlated with increased deposition of C99 in MAM domains as well as cell type-specific lipidomic alterations. Specifically, cholesterol esterification was predominant in microglia, triglyceride elevations were predominant in microglia and astrocytes, and polyunsaturated phospholipid elevations were predominant in neurons. We hypothesize that, in the acute phase, MAM upregulation serves to promote lipid synthesis for tissue repair. However, if these phenotypes are sustained (such as after multiple injuries), cognitive functions dependent on neuronal functionality could become compromised. Altogether, we propose that the induction of AD pathogenesis following brain injury may arise from chronic upregulation of MAM activities. This work advances our understanding of neurodegenerative disease etiology.