There is intense interest in understanding cellular and molecular mechanisms affected by amyloid-beta elevation, a condition that occurs in patients affected by Alzheimer's Disease (AD). Amyloid-beta is known to impair hippocampal long-term potentiation (LTP) and memory. LTP and memory are elaborate processes that require activation of a number of signaling molecules, pathways and post-translational modifications. This grant addresses the role of SUMOylation in the impairment of LTP and memory following amyloid-beta elevation. SUMOylation is a post-translational modification during which small peptides called small ubiquitin-like modifiers (SUMOs) covalently attach to lysine residues on target substrates. SUMOylation is a reversible process with various effects on protein function, including regulation of localization, stability and activity of many cellular proteins, as well as nuclear integrity, chromosomal segregation and gene expression. Moreover, SUMOylation has been implicated in the pathogenesis of several neurodegenerative disorders, including Parkinson disease, Huntington disease, and AD, but its role in AD remains to be clarified. Our approach is to combine the use of in vitro hippocampal slices and neuronal cultures with in vivo animals. This strategy offers the advantage of identifying changes of synaptic transmission in a preparation with intact neuronal circuits (slice), of giving depth to the knowledge of these changes in a more simplified system with the unique possibility of having direct access to both the pre- and the post-synaptic site (cell culture), and finally of determining whether it is possible to re-establish normal learning and memory by counteracting the effects of these changes in an in vivo complex neuronal system (the whole animal). The following aims will be addressed: 1) to determine whether upregulation of SUMOylation rescues the defect in synaptic function due to amyloid-beta elevation;2) to determine whether upregulation of SUMOylation ameliorates pre- and post- synaptic mechanisms underlying amyloid-beta-induced synaptic dysfunction;3) to determine whether upregulation of SUMOylation rescues the memory defect due to amyloid-beta elevation;and 4) to determine whether reduction of CREB SUMOylation is involved in amyloid-beta-induced synaptic and memory dysfunction. Upon the completion of these studies, we will define whether and how SUMOylation is altered in AD. Findings derived from these studies will contribute to identifying the SUMO cascade as a possible target for therapies against AD and a host of other neurodegenerative disorders characterized by amyloid-beta elevation with staggering social, economic and personal costs to the sufferers, their families and all of society.

Public Health Relevance

Alzheimer's disease is a devastating disorder that affects a large number of people, especially the elderly. Currently used therapies have limited efficacy. Early in the disease process, amyloid-beta peptides could alter the mechanisms underlying the excitatory response at single synaptic contacts producing synaptic dysfunction and abnormal memory. This project will determine whether and how amyloid-beta alters SUMOylation, a recently discovered post- translational modification that has been shown to regulate many cellular processes, in amyloid- beta induced synaptic and memory dysfunction. If this project will be successful, SUMOylation will become a possible target for developing therapies against Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS049442-08
Application #
8452710
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Corriveau, Roderick A
Project Start
2004-07-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
8
Fiscal Year
2013
Total Cost
$383,306
Indirect Cost
$115,834
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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