Imaging and Reversibility of Cellular and Network Metabolic Dysfunction in Alzheimer's Disease - PROJECT SUMMARY In Alzheimer’s disease (AD), Aβ accumulation and plaque formation precedes dementia by decades, suggesting that other downstream pathophysiological processes are responsible for precipitating symptomatic disease. Prior studies in humans reveal that brain metabolism is impaired in early AD, including an initial regional energy deficit with a superimposed, marked metabolic shift away from whole-brain and regional glycolysis. However, it is not yet clear how amyloid-induced metabolic dysfunction manifests at the cellular level and affects different cell types, how cellular metabolic dysfunction relates to tissue energy deficit and disruption of functional brain organization, and if and when this might be reversible. These questions have been difficult to answer due to technical challenges in spatiotemporally assessing cell type-specific mitochondrial function and energy metabolism, along with plaque deposition, at the microscopic and mesoscopic levels in vivo. Our central hypothesis is that plaque deposition induces metabolic dysfunction localized to specific cell types and/or cellular components. We further hypothesize that specific cellular changes in metabolic dysfunction differentially affect metabolism at the tissue level and functional brain organization at the regional and global levels. To test these hypotheses, our team has developed several technologies in mice including two-photon fluorescence lifetime imaging microscopy (TP-FLIM), multi-parametric photoacoustic microscopy (PAM), and wide-field optical imaging (WFOI). We will use these methods to measure concentrations of nicotinamide adenine dinucleotide (NADH), flavin adenine dinucleotide (FAD), cerebral metabolic rate of oxygen (CMRO2), and neural and hemodynamic activity. In addition to indicating overall mitochondrial activity, the ratio of NADH to FAD (N/F ratio) provides an optically-accessible index of metabolic shifts towards or away from glycolysis in vivo, a key early aspect of AD-related metabolic dysfunction. Since brain amyloid clearance is now readily achievable in both mice and humans, our approach will further allow us to determine whether the metabolic dysfunctions discovered from the efforts above are reduced following amyloid clearance. In the project, we aim to (Aim 1) determine the in vivo relationship between amyloid plaque deposition and cellular N/F ratio in AD mice at the microscopic level using TP-FLIM; (Aim 2) determine how amyloid plaque deposition and cellular metabolic dysfunction affect regional and global measures of tissue metabolism and functional brain organization using PAM and WFOI; and (Aim 3) determine whether amyloid plaque clearance reverses the metabolic abnormalities identified in Aims 1 and 2. Understanding the spatiotemporal relationship between Aβ accumulation, metabolic dysfunction, and functional brain organization from the cellular to systems level will be critical to revealing the mechanisms by which amyloid deposition affects downstream processes, and ultimately lead to neurodegeneration and symptomatic AD. Moreover, our study will reveal whether the metabolic dysfunction in AD is reversible or not.
