权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Imaging and Reversibility of Cellular and Network Metabolic Dysfunction in Alzheimer's Disease

阿尔茨海默病细胞和网络代谢功能障碍的成像和可逆性

基本信息

批准号：
10536491
负责人：
ADAM Q BAUER
金额：
$ 224.48万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10536491
关键词：
Address Affect Aftercare Age-Months Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid Amyloid beta-Protein Amyloid deposition Antibodies Astrocytes Biochemical Pathway Brain Cells Cerebrum Clinical Research Dementia Deposition Disease Energy Metabolism Flavin-Adenine Dinucleotide Functional disorder Future Glucose Glycolysis Human Image Imaging Techniques Impairment Lead Link Measures Metabolic Metabolic dysfunction Metabolism Methods Microglia Microscopic Microscopy Mitochondria Mus NADH Nerve Degeneration Neurons Neurosciences Nicotinamide adenine dinucleotide Optics Oxygen Pathogenesis Pathology Patients Physiological Processes Population Process Respiratory Chain Senile Plaques System Techniques Technology Testing Time Tissues Translating Treatment outcome abeta accumulation amyloid imaging awake brain metabolism calcium indicator cell type effective therapy fluorescence lifetime imaging hemodynamics human data in vivo indexing metabolic rate mitochondrial metabolism mouse model neuroimaging neuronal patterning optical imaging relating to nervous system serial imaging spatiotemporal treatment optimization two-photon

项目摘要

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.