The broad long-term goal is to elucidate the mechanisms responsible for the dysfunction and loss of neurons in degenerative neurological disorders. In Alzheimer's disease (AD) and Down syndrome (DS), age- related degeneration of basal forebrain cholinergic neurons (BFCNs) contributes significantly to dementia. Defining the molecular events leading to BFCN degeneration would significantly advance our understanding of pathogenesis. In studies on the Ts65Dn mouse, a genetic model for DS, we documented age-related degeneration of BFCNs. Nerve growth factor (NGF) is essential to the function of normal BFCNs and recent findings suggest that failed NGF signaling contributes to their degeneration of Ts65Dn. We will test the hypothesis: that a failure in NGF signaling is responsible for the degeneration (i.e. progressive dysfunction) of BFCNs in the Ts65Dn mouse. The proposed Specific Aims are: 1) To characterize the functional status of BFCNs and document age-related dysfunction of these neurons in Ts65Dn mice. Using unbiased stereology, biochemical and behavioral studies we will document the time of onset of BFCN dysfunction in Ts65Dn mice. 2) To determine if NGF signaling is defective in BFCNs in Ts65Dn and, if so, to determine whether the abnormality predate degeneration of BFCNs. Abnormal NGF retrograde transport will be used to document the existence of a signaling defect and biochemical studies will define its nature and time of onset. 3) To determine whether disrupting NGF signaling reproduces the cholinergic abnormalities seen in Ts65Dn. If the NGF signaling defect demonstrated in Aim 2 is sufficient to produce the degeneration of BFCNs in Ts65Dn, animals defective for NGF signaling should show the same degenerative events. We will examine mice treated with NGF antibodies to sequester endogenous NGF, mice in which one copy of the NGF gene has been disrupted, and mice in which both copies of the gene for the NGF TrkA receptor has been knocked-out. 4) To define NGF actions on degenerating BFCNs in Ts65Dn. Current data suggest that NGF may be capable of reversing other aspects of BFCN degeneration. In this Aim, we will determine whether NGF reverses the degenerative phenotypes defined in Aim 1. 5) To determine whether BFCN degeneration is found in other genetic models of Ds and AD and, if so, whether failed NGF signaling is present. We will examine BFCNs in several models of AD. If BFCN atrophy is detected, we will determine whether there is an abnormality of NGF signaling. We will also examine Ts65Dn animals expressing either human Apo E3 or E4 to determine whether, as expected, BFCN degeneration is worse in ApoE4 expressing mice. Evidence that abnormal NGF signaling is responsible for BFCN degeneration in models of AD and DS will give important new insights into pathogenesis and may suggest novel approaches to prevent or reverse dementia in these patients.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG016999-05
Application #
6533821
Study Section
Special Emphasis Panel (ZAG1-PKN-2)
Program Officer
Wise, Bradley C
Project Start
1998-09-15
Project End
2005-08-31
Budget Start
2002-09-01
Budget End
2005-08-31
Support Year
5
Fiscal Year
2002
Total Cost
$326,211
Indirect Cost
Name
Stanford University
Department
Neurology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Belichenko, Nadia P; Belichenko, Pavel V; Kleschevnikov, Alexander M et al. (2009) The ""Down syndrome critical region"" is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of Down syndrome. J Neurosci 29:5938-48
Belichenko, Pavel V; Kleschevnikov, Alexander M; Masliah, Eliezer et al. (2009) Excitatory-inhibitory relationship in the fascia dentata in the Ts65Dn mouse model of Down syndrome. J Comp Neurol 512:453-66
Salehi, Ahmad; Faizi, Mehrdad; Belichenko, Pavel V et al. (2007) Using mouse models to explore genotype-phenotype relationship in Down syndrome. Ment Retard Dev Disabil Res Rev 13:207-14
Wu, Chengbiao; Ramirez, Alfredo; Cui, Bianxiao et al. (2007) A functional dynein-microtubule network is required for NGF signaling through the Rap1/MAPK pathway. Traffic 8:1503-20
Belichenko, Pavel V; Kleschevnikov, Alexander M; Salehi, Ahmad et al. (2007) Synaptic and cognitive abnormalities in mouse models of Down syndrome: exploring genotype-phenotype relationships. J Comp Neurol 504:329-45
Cui, Bianxiao; Wu, Chengbiao; Chen, Liang et al. (2007) One at a time, live tracking of NGF axonal transport using quantum dots. Proc Natl Acad Sci U S A 104:13666-71
Salehi, Ahmad; Delcroix, Jean-Dominique; Belichenko, Pavel V et al. (2006) Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron 51:29-42
Miyamoto, Yuki; Yamauchi, Junji; Tanoue, Akito et al. (2006) TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology. Proc Natl Acad Sci U S A 103:10444-9
Villar, Angela J; Belichenko, Pavel V; Gillespie, Anne Marie et al. (2005) Identification and characterization of a new Down syndrome model, Ts[Rb(12.1716)]2Cje, resulting from a spontaneous Robertsonian fusion between T(171)65Dn and mouse chromosome 12. Mamm Genome 16:79-90
Howe, Charles L; Mobley, William C (2005) Long-distance retrograde neurotrophic signaling. Curr Opin Neurobiol 15:40-8

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