Repair and Regeneration in Alzheimer's Disease

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DESCRIPTION (provided by applicant): Alzheimer's disease (AD), the most common type of progressive dementia in the elderly, is characterized by neurofibrillary tangles, reactive astrocytosis, activation of microglial cells, and parenchymal deposits of beta-amyloid peptides (Abeta). The Abeta peptide (40-42 residues) is generated by the constitutive proteolytic processing of the amyloid precursor protein (APP). Several converging lines of evidence suggest that the deposition of the 42-residue form of Abeta is an early and critical event in the pathogenesis of Alzheimer's disease. Mutations in either APP, or presenilins 1 and 2 (PS), associated with familial AD (FAD) alter the cleavage of APP to favor production of the longer, more amyloidogenic, 42 residue amyloid beta peptide relative to the normally more abundant Abeta40. Together with this shift in the proportion of each Abeta species, transgenic mice co-expressing FADvariants of APP and PS1 develop Abeta deposits much earlier than mice expressing mutant APP alone. Hence, there is considerable genetic evidence to implicate amyloid deposition as one of the potential initiating insults in Alzheimer's disease. Indeed, most of the larger pharmaceutical companies and many smaller biotech enterprises are actively developing compounds that are designed to inhibit Abeta production and/or deposition. However, apart from some of the immunization studies, which we mechanistically do not understand, little is known about the capacity of mammalian brain to repair damage associated with amyloid deposition. Recently, using funds provided by a pilot project in the JHU Alzheimer's Disease Research Center, we have developed new strains of mice that express high levels of mutant APP under the transcriptional control of promoter elements that can be regulated by tetracycline. We now propose five Aims to further develop and characterize our new model and then to use these animals to ask fundamental questions regarding both the deposition of amyloid and the ability of the nervous system to repair damage caused by amyloid plaques. In a sixth Aim, we will use this new technology to create mice that express wild type and mutant tau in an effort to produce mice that model, in a regulate-able fashion, both of the major pathological aspects of Alzheimer's disease.