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:
- 金额:$ 224.48万
- 依托单位:
- 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:
- 关键词:AddressAffectAftercareAge-MonthsAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAmyloidAmyloid beta-ProteinAmyloid depositionAntibodiesAstrocytesBiochemical PathwayBrainCellsCerebrumClinical ResearchDementiaDepositionDiseaseEnergy MetabolismFlavin-Adenine DinucleotideFunctional disorderFutureGlucoseGlycolysisHumanImageImaging TechniquesImpairmentLeadLinkMeasuresMetabolicMetabolic dysfunctionMetabolismMethodsMicrogliaMicroscopicMicroscopyMitochondriaMusNADHNerve DegenerationNeuronsNeurosciencesNicotinamide adenine dinucleotideOpticsOxygenPathogenesisPathologyPatientsPhysiological ProcessesPopulationProcessRespiratory ChainSenile PlaquesSystemTechniquesTechnologyTestingTimeTissuesTranslatingTreatment outcomeabeta accumulationamyloid imagingawakebrain metabolismcalcium indicatorcell typeeffective therapyfluorescence lifetime imaginghemodynamicshuman datain vivoindexingmetabolic ratemitochondrial metabolismmouse modelneuroimagingneuronal patterningoptical imagingrelating to nervous systemserial imagingspatiotemporaltreatment optimizationtwo-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.
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.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('ADAM Q BAUER', 18)}}的其他基金
Determining the efficacy of therapeutic interventions after stroke from cell specific functional connectomes
从细胞特异性功能连接组确定中风后治疗干预的功效
- 批准号:
10586595 - 财政年份:2023
- 资助金额:
$ 224.48万 - 项目类别:
OPTOGENETIC MAPPING OF CELL SPECIFIC CONNECTIONS IN THE MOUSE BRAIN AFTER STROKE
中风后小鼠大脑中细胞特异性连接的光遗传学图谱
- 批准号:
9789702 - 财政年份:2018
- 资助金额:
$ 224.48万 - 项目类别:
OPTOGENETIC MAPPING OF CELL SPECIFIC CONNECTIONS IN THE MOUSE BRAIN AFTER STROKE
中风后小鼠大脑中细胞特异性连接的光遗传学图谱
- 批准号:
10201764 - 财政年份:2018
- 资助金额:
$ 224.48万 - 项目类别:
OPTOGENETIC MAPPING OF CELL SPECIFIC CONNECTIONS IN THE MOUSE BRAIN AFTER STROKE
中风后小鼠大脑中细胞特异性连接的光遗传学图谱
- 批准号:
10445022 - 财政年份:2018
- 资助金额:
$ 224.48万 - 项目类别:
OPTOGENETIC MAPPING OF CELL SPECIFIC CONNECTIONS IN THE MOUSE BRAIN AFTER STROKE
中风后小鼠大脑中细胞特异性连接的光遗传学图谱
- 批准号:
9661800 - 财政年份:2018
- 资助金额:
$ 224.48万 - 项目类别:
MECHANISMS OF FUNCTIONAL AND BEHAVIORAL RECOVERY FOLLOWING ISCHEMIC STROKE
缺血性中风后功能和行为恢复的机制
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9037714 - 财政年份:2014
- 资助金额:
$ 224.48万 - 项目类别:
MECHANISMS OF FUNCTIONAL AND BEHAVIORAL RECOVERY FOLLOWING ISCHEMIC STROKE
缺血性中风后功能和行为恢复的机制
- 批准号:
9244074 - 财政年份:2014
- 资助金额:
$ 224.48万 - 项目类别:
MECHANISMS OF FUNCTIONAL AND BEHAVIORAL RECOVERY FOLLOWING ISCHEMIC STROKE
缺血性中风后功能和行为恢复的机制
- 批准号:
8812912 - 财政年份:2014
- 资助金额:
$ 224.48万 - 项目类别:
MECHANISMS OF FUNCTIONAL AND BEHAVIORAL RECOVERY FOLLOWING ISCHEMIC STROKE
缺血性中风后功能和行为恢复的机制
- 批准号:
8700071 - 财政年份:2014
- 资助金额:
$ 224.48万 - 项目类别:
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