Our studies aim to define the genetic and molecular bases for the degeneration of specific neuronal populations in the brains of elderly Down syndrome (DS) patients. The principal focus of this application is the degeneration of basal forebrain cholinergic neurons (BFCNs), whose age-related loss contributes significantly to dementia in both Alzheimer's disease (AD) and DS patients. Defining the pathogenesis of BFCN degeneration may lead to treatments that reverse or prevent dementia. In studies leading to this application, we examined the Ts65Dn mouse, a genetic model for DS in which the mouse chromosome 16 (MMU16) homolog to the DS critical region is found in three copies. We documented behavioral, morphological, and biochemical phenotypes shared by Ts65Dn mice and S patients. Importantly, these mice showed age- related degeneration of BFCNs. Our recent findings suggest that a failure in NGF signaling contributes to BFCN degeneration. Moreover, we showed that infusion of exogenous NGF reversed the degenerative changes. We propose to test the hypothesis: that a failure in NGF signaling is responsible for the degeneration (i.e. progressive dysfunction) of BFCNs in the Ts65Dn mouse. We have powerful new tools to aid us in testing the hypothesis, two new partial trisomic mice, Ms1Ts65 and Ts1Cje. We will document abnormalities in NGF signaling, BFCN function and cholinergically-influenced cognitive behaviors in Ts65Dn and ask if they co-segregate in the new trisomies. Co-segregation will suggest that increased dosage of the same gene(s) responsible for all three phenotypes. This will support the hypothesis, as will evidence that NGF treatment reverse BFCN degeneration and improves cholinergically- influenced behaviors. We propose the following Specific Aims: 1) To characterize NGF signaling in Ts65Dn, and to map abnormalities to either Ts1Cje or Ms1Ts65. We will define the NGF signaling defect, determine the molecular basis for the abnormality, and map it genetically. 2) To characterize the functional status of BFCNs in Ts65Dn in Ts65Dn, and to map age-related cholinergic degeneration to either Ts1Cje or Ms1Ts65. We will further characterize BFCN dysfunction in Ts65Dn mice and define which aspects of BFCN synaptic and perikaryal function map to Ts1Cje and Ms1Ts65. 3) To characterize cholinergically-influenced cognitive behaviors in Ts65Dn, and to map age-related abnormalities to either Ts1Cje or Ms1Ts65. We will characterize cognitive changes in aging Ts65Dn mice, focusing on those influenced by BFCNs. Abnormalities will be mapped in studies on Ts1Cje and Ms1Ts65. 4) To attempt to reverse with NGF treatment the dysfunction of BFCNs and abnormal cholinergically-influenced behaviors in Ts65Dn, Ts1Cje and Ms1Ts65. If the hypothesis is correct, we will see that NGF treatment reverse many, and perhaps all, the BFCN and cholinergically-influenced behavioral abnormalities that map with NGF signaling abnormalities. We believe that the proposed studies will provide important new perspectives on the neurobiology of DS. Moreover, the long-lived and productive collaboration of the Mobley and Epstein laboratories, and the availability of uniquely important animal resources will allow considerable progress in defining important DS phenotype-genotype relationships.
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