Mitochondrial and synaptic dysfunction is early pathological features of the Alzheimer's disease (AD)-affected brain. Perturbed bioenergetics function, respiration failure, aberrant mitochondrial dynamics, and increased levels of reactive oxygen species (ROS) are observed in brains and peripheral tissues including platelets of subjects with AD. RAGE (Receptor for Advanced Glycation Endproducts, AGEs) functions as a signal transducing cell surface acceptor site for AGEs, S100/calgranuline, or amyloid-beta peptide (A). Interaction of RAGE and its ligands increases oxidative stress, inflammation, A? accumulation, and impairs synaptic function and learning memory. However, the impact of RAGE on tau- and A?-mediated mitochondrial stress, tau pathology, tau-induced synaptic and cognitive dysfunction in AD remains unclear. It is unclear whether and how RAGE-dependent signal transduction contributes to alterations in mitochondrial structure and function in AD. The proposed studies will test the hypothesis that RAGE functions as signal transduction to perturb mitochondrial structure and function, and oxidative stress, leading to synaptic mitochondrial and synaptic dysfunction. This proposal will address the fundamental questions of whether RAGE is a key player in AD-related aberrant mitochondria and synaptic injury and whether blockade of RAGE restores mitochondrial and neuronal function.

Public Health Relevance

The aim of this project is to investigate a role of RAGE in mitochondrial and tau pathology, leading to synaptic injury relevant to the pathogenesis of Alzheimer's disease. This proposal will address the fundamental questions of whether RAGE is a key player in AD-related aberrant mitochondria and synaptic injury and whether blockade of RAGE restores mitochondrial and neuronal function.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
7R01AG061324-02
Application #
9856955
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Wise, Bradley C
Project Start
2019-02-01
Project End
2023-11-30
Budget Start
2020-06-01
Budget End
2020-11-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Surgery
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032