Aging-associated cognitive decline is a frequent condition among individuals aged 60 and over, with prevalence estimated at 20-27%, and is of high use for the identification of preclinical stages of dementia. Deficits in memory tasks are often related to dysfunctions of the hippocampus and cholinergic neurons projecting to the hippocampus and cortex. While present therapies for neurodegeneration and cognitive deficits are focused on neuroprotection from oxidative stress and supporting acetylcholine neurotransmission, this project proposes a change of paradigm towards proteolytic processing of pro-neurotrophins. The balance between neurotrophins and their precursors regulates critically important processes in developing and adult brains, including neuronal survival, synaptogenesis and synaptic plasticity, and may play important roles in preventing aging-related degeneration. We will study the role of proBDNF in hippocampal neuron dysfunctions underlying aging-related memory impairment using a multilevel approach: behavioral, pharmacological, biochemical and neuroanatomical. We will investigate proBDNF processing in the aged versus young mouse hippocampus, and we will evaluate correlations between BDNF signaling and memory deficits in a behavioral task. We will also pharmacologically manipulate proBDNF processing in order to improve memory performance in aged animals. Should this study be successful, it would impact future therapies aimed at preserving memory performance in aged individuals by identifying a new set of molecular pathways to be targeted by therapy.

Public Health Relevance

Aging-associated cognitive decline is a frequent condition among individuals aged 60 and over, with prevalence estimated at 20-27%, and is of high use for the identification of preclinical stages of dementia. Deficits in memory tasks are often related to dysfunctions of the hippocampus and cholinergic neurons projecting to the hippocampus and cortex. Our studies will investigate a molecular pathway to be targeted by future therapies aimed at preserving memory performance in aged individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG038767-02
Application #
8277213
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Wagster, Molly V
Project Start
2011-07-01
Project End
2012-08-06
Budget Start
2012-07-01
Budget End
2012-08-06
Support Year
2
Fiscal Year
2012
Total Cost
$12,100
Indirect Cost
$3,897
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425