Uncovering Region-Specific Lipid and Bioenergetic Alterations in Aging and Alzheimer's Disease Through High-Resolution Spatial Metabolomics

Abstract

Despite the decades of research into Alzheimer’s Disease (AD), a neurodegenerative disorder growing in prevalence, an effective treatment option has remained elusive. Previous studies which have analyzed the disorder from a metabolic perspective have treated brain regions shown to be structurally heterogenous as singular units. Two regions relevant to the ongoing discussion of AD whose sub-regional variation have been overlooked are the white matter fiber tracts and cerebellar layers. This thesis applies matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) at a spatial resolution of 10 μm to resolve the lipid and metabolite profiles of these sub-regions, and how they change with aging and AD. Three distinct datasets were analyzed: a base-line wild-type, an aging comparison (2-month vs 26-month C57BL/6J), and an AD comparison (age-matched 15-month-old control vs 5XFAD). A principal component analysis established variation between the anterior and posterior fiber tracts as well as the molecular and granular cerebellar layers. In the aging analysis, low NAD+/NADH ratios in posterior brain regions were mechanistically tied to energy state (ADP/ATP and AMP/ATP ratios) and reduced unsaturated fatty-acid (FA) decline via a compensatory pathway sustaining FA desaturation. When applying this pathway to the AD mouse model, sharp declines in FAs were observed in posterior regions despite low NAD+/NADH values. The dysfunction of the Electron Transport Chain (ETC) which causes a rapid accumulation of NADH and disrupts ATP production was suggested as the driver against the activation of the compensatory lipid metabolism pathway.