Axonal transport and Alzheimer's Disease pathogenesis

University Of California, San Diego, La Jolla CA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Several Alzheimer's Disease (AD)-related proteins, such as amyloid precursor protein (APP) and presenilin (PS1), have been shown to be involved in axonal transport. Mouse models of both intracellular transport defects and AD, as well as preliminary data on early AD human brain cholinergic neurons, all exhibit axonal swellings typical of vesicle and organelle accumulation and disrupted axonal transport. Reducing axonal transport in AD models exacerbates this phenotype, as well as plaque formation. This research proposal aims to test the hypothesis that defects in axonal transport contribute to the early neurodegeneration associated with AD. Human AD cholinergic axonal pathology will be correlated with AD progression, synaptic failures, and cognitive deficits. Study of a mouse wildtype APP overexpression model will test if motor protein receptor overexpression causes axonal pathology. Mutant human APP and PS1 will reveal if altered motor receptor processing is sufficient to cause the same axonal. pathology. The relative timing of neuronal pathology, synapse loss, and their correlation with cognitive deficits and plaque deposition will be crucial in understanding the order and likely cause-effect relationships of pathological events. [unreadable] [unreadable] [unreadable]