DESCRIPTION (provided by applicant): Accumulation of the small A beta peptide in the brain in beta-amyloid plaques is an invariant feature of Alzheimer's disease (AD), the most common type of neurodegeneration affecting over six million Americans. Abeta is derived from the amyloid precursor protein by proteolytic processing of the amyloid precursor protein (APP). Individuals with Down syndrome (DS; trisomy 21) inevitably develop AD pathology, including beta-amyloid plaques, in their fourth or fifth decade of life. The App gene is located on human chromosome 21, and it is generally thought that this additional gene copy of App mechanistically leads to AD in DS individuals. Using mouse models of human DS such as the Ts65Dn mouse, which is trisomic for a segment of murine chromosome 16 orthologous to the DS critical region of human chromosome 21, the metabolism of APP and the production of Abeta will be examined in the intact CNS. APP metabolite levels will be determined as a function of aging in the Ts65Dn mouse, and alterations in the rate of APP and APP metabolite (secretory APP fragments, C-terminal APP fragments, Abeta) turnover in vivo in the Ts65Dn mouse will be examined (Aim 1). The Ts65Dn mouse also shows abnormalities in endocytosis seen selectively in AD and DS and age-dependent basal forebrain cholinergic neuron degeneration. Given that it has been previously shown that APP proteolytic processing can occur in early endosomes, the link between neuronal endocytosis alterations in the Ts65Dn model and APP metabolism will be examined using immunolocalization techniques as well as subcellular fractionation (Aim 2). The hypothesis that APP mismetabolism in the Ts65Dn mouse is mechanistically linked to neurodegeneration will be tested by reducing Abeta levels in the CNS using passive vaccination with an anti-murine Abeta monoclonal antibody (Aim 3), thereby establishing a connection between neurodegeneration and Abeta levels/APP mismetabolism in this model. These studies will characterize in vivo brain APP metabolism and test the idea that APP mismetabolism is a cause of basal forebrain cholinergic neurodegeneration in a DS model. These findings will have important implication for the mechanisms of AD pathogenesis in DS and may suggest common modalities of neurodegeneration with AD.