A central goal of research in Alzheimer's disease (AD) is the identification and reversal of the earliest pathological changes in affected brain systems and neural circuits. Although numerous structural and biochemical changes have been documented in late-stage AD brains, the early microscopic events that initiate neuronal dysfunction provide potentially more attractive therapeutic targets. Among the initial targets of AD pathogenesis are neuronal synapses. In its earliest phases, AD is characterized by a remarkably pure impairment of memory that has been attributed to 'subpathological' alterations in excitatory synaptic transmission in the hippocampus. Recent studies strongly support the involvement of misprocessed amyloid precursor protein (APP) and A-beta deposition in the early synaptic and cognitive changes of AD. However, little is known about the molecular mechanisms by which exposure to A-beta affects synaptic plasticity, or potential compensatory mechanisms that could be used to counteract aberrant plasticity. In the proposed research, we will define the molecular targets for A-beta-induced synaptic dysfunction. A newly recognized mechanism for changing synaptic strength is the rapid removal of postsynaptic receptors via endocytosis. We have recently found that dendritic spines contain a zone of clathrin assembly and endocytosis adjacent to, but spatially segregated from, the postsynaptic density. Moreover, we have found that the protein machinery for postsynaptic endocytosis is functionally altered by aging and may be upregulated by exposure to A-beta. These findings present an opportunity to clarify in molecular detail the mechanisms by which A-beta influences excitatory transmission and synaptic plasticity. These studies will provide much-needed insight into the cell biological mechanisms that underlie AD-related changes in synaptic plasticity, and will identify molecular signaling pathways that may correct A-beta-induced changes in synaptic function. As such, the proposed research holds promise for the development of new therapeutic approaches for AD-associated memory loss and cognitive deficit.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG024492-04
Application #
7257052
Study Section
Special Emphasis Panel (ZRG1-CDIN (01))
Program Officer
Snyder, Stephen D
Project Start
2004-09-15
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$266,121
Indirect Cost
Name
Duke University
Department
Biology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Kennedy, Matthew J; Davison, Ian G; Robinson, Camenzind G et al. (2010) Syntaxin-4 defines a domain for activity-dependent exocytosis in dendritic spines. Cell 141:524-35
Yashiro, Koji; Riday, Thorfinn T; Condon, Kathryn H et al. (2009) Ube3a is required for experience-dependent maturation of the neocortex. Nat Neurosci 12:777-83
Wang, Zhiping; Edwards, Jeffrey G; Riley, Nathan et al. (2008) Myosin Vb mobilizes recycling endosomes and AMPA receptors for postsynaptic plasticity. Cell 135:535-48
Blanpied, Thomas A; Kerr, Justin M; Ehlers, Michael D (2008) Structural plasticity with preserved topology in the postsynaptic protein network. Proc Natl Acad Sci U S A 105:12587-92
Lu, Jiuyi; Helton, Thomas D; Blanpied, Thomas A et al. (2007) Postsynaptic positioning of endocytic zones and AMPA receptor cycling by physical coupling of dynamin-3 to Homer. Neuron 55:874-89
Ehlers, Michael D; Heine, Martin; Groc, Laurent et al. (2007) Diffusional trapping of GluR1 AMPA receptors by input-specific synaptic activity. Neuron 54:447-60
Park, Mikyoung; Salgado, Jennifer M; Ostroff, Linnaea et al. (2006) Plasticity-induced growth of dendritic spines by exocytic trafficking from recycling endosomes. Neuron 52:817-30