his new application is to request five years of support for an interdisciplinary investigation of hippocampal mechanisms mediating memory. Understanding these mechanisms is vital because their impairment appears to underlie the memory deficits seen in aging and in Alzheimer's disease. From rodents to humans, the hippocampus and adjacent interconnected structures are principally concerned with memory. While the anatomical connectivity within the subfields of the hippocampus is reasonably well delineated, how each of the subfields contribute to learning and memory functions are not clear. At the same time, neurons within the substructures are susceptible to damage and death following injury such as cerebral ischemia, in aging and in certain neurodegenerative diseases such as Alzheimer's disease. In particular, consistent presence of Alzheimer associated pathological lesions in this structure isolates the hippocampus from its cortical connectivity. Consequently, the selective vulnerability of this brain region is likely responsible for the cardinal manifestations of memory impairment in Alzheimer's disease. The working hypothesis that guides this program is that perturbations of axonal and synaptic compartments, either through structural or functional damage, lead to early synaptic dysfunction and result in learning and memory deficits in aging and neurodegeneration. This program will focus on the hippocampus proper, particularly the CA1 and CAS regions with two major goals in mind. First, we will examine the core learning and memory functions of these two subregions of the hippocampus using a novel, selective, and transient inactivation of these neurons through a combination of genetic and pharmacologic means. These manipulations will use exciting new technology developed at The Salk Institute and will allow us to reversibly probe the function of CA1 and CA3 subregions in learning and memory not previously possible. Second, we will investigate the mechanisms responsible for axonal and synaptic changes in this region, particularly in Alzheimer's disease related neurodegeneration. Specifically, we will examine cultured neurons and various mouse models to test several mechanisms that may contribute to hippocampal injury that are initiated by the amyloid beta-protein and the amyloid precursor protein. We propose that both amyloid precursor protein and various proteolytic products, including amyloid beta-protein, contribute in different ways to synaptic and axonal damage in Alzheimer's disease. By bringing together laboratories with unique expertise and background, we propose to probe the hippocampus in memory and in neurodegeneration by a multi-disciplinary approach. Further, a unique and key aspect of this Program is the sharing of common mouse strains, reagents, and vectors to facilitate the collaborative studies proposed in our four Projects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG032180-01
Application #
7487635
Study Section
Special Emphasis Panel (ZAG1-ZIJ-3 (J1))
Program Officer
Snyder, Stephen D
Project Start
2007-09-15
Project End
2012-08-31
Budget Start
2007-09-15
Budget End
2008-08-31
Support Year
1
Fiscal Year
2007
Total Cost
$316,725
Indirect Cost
Name
University of California San Diego
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Weissmiller, April M; Natera-Naranjo, Orlangie; Reyna, Sol M et al. (2015) A ?-secretase inhibitor, but not a ?-secretase modulator, induced defects in BDNF axonal trafficking and signaling: evidence for a role for APP. PLoS One 10:e0118379
Neumann, Sylvia; Campbell, George E; Szpankowski, Lukasz et al. (2014) Characterizing the composition of molecular motors on moving axonal cargo using ""cargo mapping"" analysis. J Vis Exp :e52029
Almenar-Queralt, Angels; Falzone, Tomas L; Shen, Zhouxin et al. (2014) UV irradiation accelerates amyloid precursor protein (APP) processing and disrupts APP axonal transport. J Neurosci 34:3320-39
Gunawardena, Shermali; Yang, Ge; Goldstein, Lawrence S B (2013) Presenilin controls kinesin-1 and dynein function during APP-vesicle transport in vivo. Hum Mol Genet 22:3828-43
Sibilski, Claudia; Mueller, Thomas; Kollipara, Laxmikanth et al. (2013) Tyr728 in the kinase domain of the murine kinase suppressor of RAS 1 regulates binding and activation of the mitogen-activated protein kinase kinase. J Biol Chem 288:35237-52
Almenar-Queralt, Angels; Kim, Sonia N; Benner, Christopher et al. (2013) Presenilins regulate neurotrypsin gene expression and neurotrypsin-dependent agrin cleavage via cyclic AMP response element-binding protein (CREB) modulation. J Biol Chem 288:35222-36
Woodruff, Grace; Young, Jessica E; Martinez, Fernando J et al. (2013) The presenilin-1 ?E9 mutation results in reduced ?-secretase activity, but not total loss of PS1 function, in isogenic human stem cells. Cell Rep 5:974-85
Rodrigues, Elizabeth M; Weissmiller, April M; Goldstein, Lawrence S B (2012) Enhanced ýý-secretase processing alters APP axonal transport and leads to axonal defects. Hum Mol Genet 21:4587-601
Young, Jessica E; Goldstein, Lawrence S B (2012) Alzheimer's disease in a dish: promises and challenges of human stem cell models. Hum Mol Genet 21:R82-9
Szpankowski, Lukasz; Encalada, Sandra E; Goldstein, Lawrence S B (2012) Subpixel colocalization reveals amyloid precursor protein-dependent kinesin-1 and dynein association with axonal vesicles. Proc Natl Acad Sci U S A 109:8582-7

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