In Alzheimer?s disease, axons are frequently the first part of a neuron to be affected. Neurodegenerative stimuli trigger local signaling pathways that cause the retrograde spread of disease. We have found that application of beta-amyloid within minutes triggers the intra-axonal synthesis of proteins that form a unique transcription factor complex. The formation and function of this complex is required for the induction of neurodegeneration in response to the AD-related peptide oligomeric A?1-42. The appearance of this transcription factor complex in human postmortem brain tissue is restricted to AD brains. Here, we propose that the presence of this transcription factor complex in the central nervous system is a hallmark of age-related neurodegenerative disorders, including Alzheimer?s disease. With the experiments in this proposal we will investigate the relevance of the disease-specific transcription factor complex for the various pathological manifestations of Alzheimer?s disease, and we will study which genes are up- or downregulated by it. We will contrast these results from Alzheimer?s disease brain with findings in Parkinson?s disease brain, to determine how signaling via the complex differs in distinct neurodegenerative disorders. Using genetic and pharmacological approaches, we will investigate in mouse models of Alzheimer?s disease, whether interference with the disease-specific transcription factor complex slows down or prevents disease progression. Together, the results from this research project will establish a novel mechanism by which neurons react to oligomeric A?1-42. Our results will provide the rationale for targeting this signaling mechanism and test the feasibility of such an approach.

Public Health Relevance

Alzheimer?s disease is a progressive neurodegenerative disorder in which pathological changes spread through the brain. We have found that this spread is at least partially mediated by a transcription factor complex that is specifically upregulated in neurodegenerative conditions. Here, we propose to study the functional consequences of this complex; the results obtained from this research program will have relevance for the understanding of the etiology of AD and might outline a novel avenue for future therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS109607-01
Application #
9641667
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Corriveau, Roderick A
Project Start
2018-09-15
Project End
2023-06-30
Budget Start
2018-09-15
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032