PROJECT 3: KOO/ROY - ABSTRACT The amyloid precursor protein (APP) is sequentially cleaved by ?- and ?-secretases to generate amyloid ?-peptide (A?) in the brain - a central player in the amyloid cascade hypothesis. APP cleavage by ?-secretase-1 (BACE-1) is the rate-limiting step for production of A?. A? is believed to exert its toxicity on neurons while in a soluble and oligomeric state, prior to deposition as insoluble fibrils in brain. Thus, for reasons related to both pathophysiology and therapeutics, understanding mechanisms and pathways of A? generation from APP is a major focus of many laboratories. An intriguing aspect of A? production is that its release is dependent upon neuronal activity - enhanced synaptic activity results in more A? release. Though pathways involved in trafficking and cleavage of APP in neurons are of obvious importance, the vast majority of previous studies on APP/BACE-1 trafficking have been carried out in non-neuronal cells. These findings may not always be applicable to neurons, which are highly polarized and are known to have very different trafficking mechanisms. Furthermore, inferences on how neuronal activity modulates APP processing by BACE-1 require work in neurons. The prevailing view is that at presynaptic terminals, heightened synaptic vesicle recycling that accompanies high synaptic activity results in increased internalization into endosomes of APP where proteolysis by secretases take place. However, our recent studies using live neuronal imaging showed rather surprising results in that APP and BACE-1 normally traffic in distinct vesicles - perhaps preventing unabated cleavage - but converge in dendrites upon activity-induction. This led us to propose a new model whereby neuronal activity brings together APP and BACE-1 in dendrites where the two molecules interact. Only subsequently are these two molecules sorted into axons to distal terminals. Accordingly, this Project will examine a number of predictions that emanate from this working model and will allow us to refine the trafficking pathways of APP and BACE-1 and define how they relate to amyloidogenesis in neurons in an activity-dependent manner.
Four Aims are proposed: 1) test the hypothesis that APP and BACE-1 are first sorted to dendrites immediately after biosynthesis, 2) determine the subcellular sites where APP and BACE-1 interact and correlate this to sites of A? release, 3) test the hypothesis that APP and BACE-1 are transcytosed from dendrites to axons, possibly in an activity dependent manner, and 4) utilize tissue from the Neuro-pathology Core to assess whether the colocalization of APP and BACE-1 is preferential to the "default mode network" brain regions which are known to be sites of A? deposits. Collectively, results from these studies will provide new insights into the trafficking pathways of APP and BACE-1 and demonstrate how neuronal activity modulates these pathways to enhance APP cleavage and A? release.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
2P50AG005131-31
Application #
8676149
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4 (J1))
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
31
Fiscal Year
2014
Total Cost
$157,500
Indirect Cost
$32,500
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Ronquillo, Jay Geronimo; Baer, Merritt Rachel; Lester, William T (2016) Sex-specific patterns and differences in dementia and Alzheimer's disease using informatics approaches. J Women Aging 28:403-11
Ridge, Perry G; Hoyt, Kaitlyn B; Boehme, Kevin et al. (2016) Assessment of the genetic variance of late-onset Alzheimer's disease. Neurobiol Aging 41:200.e13-20
Ringman, John M; Monsell, Sarah; Ng, Denise W et al. (2016) Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database. J Neuropathol Exp Neurol 75:284-90
Besser, Lilah M; Alosco, Michael L; Ramirez Gomez, Liliana et al. (2016) Late-Life Vascular Risk Factors and Alzheimer Disease Neuropathology in Individuals with Normal Cognition. J Neuropathol Exp Neurol 75:955-962
Burke, Shanna L; Maramaldi, Peter; Cadet, Tamara et al. (2016) Neuropsychiatric symptoms and Apolipoprotein E: Associations with eventual Alzheimer's disease development. Arch Gerontol Geriatr 65:231-8
de Wilde, Martijn C; Overk, Cassia R; Sijben, John W et al. (2016) Meta-analysis of synaptic pathology in Alzheimer's disease reveals selective molecular vesicular machinery vulnerability. Alzheimers Dement 12:633-44
John, Samantha E; Gurnani, Ashita S; Bussell, Cara et al. (2016) The effectiveness and unique contribution of neuropsychological tests and the δ latent phenotype in the differential diagnosis of dementia in the uniform data set. Neuropsychology 30:946-960
Bonham, Luke W; Geier, Ethan G; Fan, Chun C et al. (2016) Age-dependent effects of APOE ε4 in preclinical Alzheimer's disease. Ann Clin Transl Neurol 3:668-77
Ting, Simon Kang Seng; Hao, Ying; Chia, Pei Shi et al. (2016) Clinicopathological correlation of psychosis and brain vascular changes in Alzheimer's disease. Sci Rep 6:20858
Valera, Elvira; Masliah, Eliezer (2016) Combination therapies: The next logical Step for the treatment of synucleinopathies? Mov Disord 31:225-34

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