Alzheimer's disease (AD) features the dysfunction and loss of basal forebrain cholinergic neurons (BFCNs) whose degeneration contributes to cognitive difficulties. The long term goal of this project is to define the cellular and molecular basis for the degeneration of BFCNs. One clue is that the hallmarks of AD, including BFCN degeneration, are present in elderly people with Down syndrome (DS) (i.e. trisomy 21), many of whom also show progressive cognitive decline. To link increased expression of one or more pf the genes on chromosome 21 to BFCN degeneration examined the Ts65Dn mouse, a genetic model for DS. We showed that degeneration of BFCNs is linked to failed retrograde axonal transport of nerve growth factor (NGF). In recent studies, we showed that failed NGF transport and degeneration of BFCNs are caused by increased expression of the gene for the amyloid precursor protein (APR), present in three copies in these mice. The defect in transport was recapitulated in mice transgenic either for wild type human APR or for a mutant APR that causes AD. Preliminary data suggest that increased APR C-terminal fragments (CTFs) within endosomes disrupts NGF transport. Our hypothesis is that in DS an increase in full length APR, and/or its transmembrane C-terminal fragments (CTFs), within endosomes acts to inhibit retrograde transport of NGF and NGF-TrkA signaling leading to neuronal dysfunction and degeneration. Using Ts65Dn and transgenic APR mice we will: 1) characterize further the defects in axonal structure and function that result from increased expression of APR;2) determine whether or not increased expression of APR decreases NGF- TrkA signaling in the axons and cell bodies of BFCNs and to define the cellular compartment involved;3) show whether or not failed NGF-TrkA signaling is responsible for BFCN degeneration and abnormal hippocampal learning;and 4) define in vitro the mechanism by which APR overexpression acts. Using a culture system that allows for precise tracking of NGF transport, and building upon preliminary studies showing that Ts65Dn DRG neurons also show a marked deficit in NGF transport, we will determine which APR isoforms are responsible for disrupted transport and signaling and discern the mechanism(s) employed. These studies are an important first step in clarifying the pathogenesis of BFCN neurodegeneration in the setting of increased APR expression and may motivate novel treatment strategies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neural Degenerative Disorders and Glial Biology Study Section (NDGB)
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Mamounas, Laura
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Kleschevnikov, Alexander M; Yu, Jessica; Kim, Jeesun et al. (2017) Evidence that increased Kcnj6 gene dose is necessary for deficits in behavior and dentate gyrus synaptic plasticity in the Ts65Dn mouse model of Down syndrome. Neurobiol Dis 103:1-10
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Ruparelia, Aarti; Pearn, Matthew L; Mobley, William C (2012) Cognitive and pharmacological insights from the Ts65Dn mouse model of Down syndrome. Curr Opin Neurobiol 22:880-6
Kleschevnikov, Alexander M; Belichenko, Pavel V; Faizi, Mehrdad et al. (2012) Deficits in cognition and synaptic plasticity in a mouse model of Down syndrome ameliorated by GABAB receptor antagonists. J Neurosci 32:9217-27
Kleschevnikov, A M; Belichenko, P V; Salehi, A et al. (2012) Discoveries in Down syndrome: moving basic science to clinical care. Prog Brain Res 197:199-221
Rissman, Robert A; Mobley, William C (2011) Implications for treatment: GABAA receptors in aging, Down syndrome and Alzheimer's disease. J Neurochem 117:613-22
Sung, Kijung; Maloney, Michael T; Yang, Jingkun et al. (2011) A novel method for producing mono-biotinylated, biologically active neurotrophic factors: an essential reagent for single molecule study of axonal transport. J Neurosci Methods 200:121-8

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