Amyloid precursor protein (APR) is a key player in the development of Alzheimer's Disease (AD) Mutations in humans that alter APR processing or overexpress APP appear to be sufficient to cause AD and to generate the amyloid plaques that are a constent feature of AD neuropathology. Although most work on AD development focuses on the potential toxicity of Abeta proteolytic fragments of APP, numerous observations point to significant neuronal defects caused by other APP proteolytic processing products or overexpression of full length APP itself. A consistent and long-standing set of observations suggest that a highly relevant phenotype caused by excess APP, which may also be found in early and late AD, is poisoning of the axonal transport machinery. This machinery is required for long-range neurotrophic signaling and for the supply of proteins and organelles needed for the maintenance of functional synapses. These observations also provide a way to tie APP behavior to the other major neuropathology found in AD, namely the neurofibrillary tangles, composed of the microtubule binding protein tau, which has also been implicated in controlling the transport of APP and other vesicles and organelles. Because overexpression of mutant forms of human APP in the mouse is one of the major models of AD, and because overexpression of APP may be sufficient to cause some forms of AD, it is crucial to understand the consequences of APP overexpression in neurons, and in particular how excess APP poisons axonal transport. Key issues include resolving whether Abeta plays a role in axonal transport defects and whether the defects generated by APP overexpression and Abeta toxicity are distinct. A related issue that needs to be evaluated further emerges from our recent observation that transport defects may enhance APP processing, potentially causing an autocatalytic spiral of defects. To understand the consequences of APP overexpression in neurons, and in particular how excess APP poisons axonal transport and to resolve whether Abeta plays a role in causing axonal transport defects we propose: 1) To test the hypothesis that APP controls its own transport in """"""""cis"""""""". 2) To test the hypothesis that increased APP or its processing products poisons transport in trans and consequently affects synaptic function, and behavior. 3) To test the hypothesis that reduced transport enhances APP processing in neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG032180-05
Application #
8132465
Study Section
Special Emphasis Panel (ZAG1-ZIJ-3 (J1))
Program Officer
Refolo, Lorenzo
Project Start
2007-09-15
Project End
2012-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$332,435
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
Reis, Gerald F; Yang, Ge; Szpankowski, Lukasz et al. (2012) Molecular motor function in axonal transport in vivo probed by genetic and computational analysis in Drosophila. Mol Biol Cell 23:1700-14
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
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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