Alzheimer's disease (AD) is a devastating illness that erodes the mind, progressively leading to incapacitating dementia and eventually death. The cause and progression of the disease are not well understood, and there is currently no known cure. One hallmark of AD pathology in the brain is the accumulation and aggregation of amyloid beta peptide (A?42), a cleavage product of the APP protein by the ?- secretase transmembrane protease, into extracellular amyloid plaques. These are thought to contribute to synapse degeneration, disrupted calcium homeostasis, and neuronal death. We have identified a novel developmental pathway promoting dendritic growth in response to neuronal activity, which involves ?-secretase. Our goal is to elucidate this pathway, its developmental importance, and potential dysregulation in the adult to provide new therapeutic targets and interventional tools fo treatment of AD. During neural development, axons and dendrites grow and connect in a dynamic process of extension and retraction, where final connections are selected based on salient activity pattern. In the adult, activity- dependent structural rearrangements are thought t underlie sensory map plasticity and the formation of novel connections during learning. These changes in neuronal structure and function are mediated by the transcriptional activation of specific genes which are responsive to synaptic activity. Our lab has previously identified a large number of these candidate plasticity genes (CPGs), whose expression is up-regulated in response to activity. We have identified two CPGs, tspan5 and ptprm, which affect structural remodeling of inhibitory neurons, and both of these genes have both been shown to interact with ?-secretase. We propose that the expression of tspan5 and ptprm plays an important role in dendritic outgrowth and structural remodeling during development, that they later contribute to adult activity-dependant plasticity, and that their dysregulation in the adult may contribute to AD We propose to study this pathway using biochemical and cell biological techniques to test the interaction of Tspan5, Ptprm, and ?-secretase both in vitro and in vivo. By altering the expression levels of tspan5 and ptprm we will determine their effects on structural remodeling. We will also use a mouse model of Alzheimer's disease to determine if changing tspan5 or ptprm expression levels can rescue cellular abnormalities and/or cognitive defects characteristic of AD.

Public Health Relevance

Alzheimer's disease (AD) is a devastating illness that erodes the mind, progressively leading to incapacitating dementia and eventually death. There is an urgent need to discover new targets for therapeutic development based on an understanding of the cellular mechanisms that underlie the disease. We have identified two new targets which are known to interact with a key enzyme implicated in AD, ?-secretase, and the experiments proposed here will further define their function in the context of developmental neuronal outgrowth and in AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AG044061-02
Application #
8634502
Study Section
Special Emphasis Panel (ZRG1-F03A-N (20))
Program Officer
Refolo, Lorenzo
Project Start
2012-09-14
Project End
2015-09-13
Budget Start
2013-09-14
Budget End
2014-09-13
Support Year
2
Fiscal Year
2013
Total Cost
$42,232
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139