Alzheimer's disease (AD) is a progressive, fatal neurodegenerative disorder of the elderly. It is of growing social concern because a larger percentage of the world's population is becoming elderly, and therefore at greater risk for developing this disease. AD is characterized clinically by dementia and behavioral abnormalities, and pathologically by the accumulation of the amyloidogenic Abeta fragment of the amyloid precursor protein (APP) in the cerebral cortex and hippocampus, the presence of neurofibrillary tangles in pyramidal neurons predominantly located in the neocortex and nucleus basalis of Meynert, and by neuronal loss and gliosis. There has been no truly representative animal model for research on AD. To provide this essential tool for animal studies of AD, we have overexpressed a mutant human APP in transgenic (Tg) mice, and created several lines of mice which develop a neurobehavioral disorder accompanied by premature death. Hypertrophic astrocytosis in the hippocampus and cerebral cortex colocalizing with ectopic intracellular accretions of APP/Abeta protein in pyramidal neurons were identified in three founder mice expressing mutant APP which died with this disorder, but not in Tg mice expressing wild-type APP. Do these mice have Alzheimer's disease? Our preliminary results are encouraging, but further studies are needed to answer this question.
The specific aims of this proposal are: * to determine whether these Tg mice have AD or an AD-like illness; and * to create the best possible representation of AD in mice by producing a variety of Tg lines expressing different APP mutations, isoforms, and homologues. We propose to characterize the clinical and pathological phenotype in these mice by the following methods: (a) careful clinical observation of animals aided by a rapid test for exploratory behavior which thus far correlates with mutant transgene copy number, premature death, and neuropathologic findings; (b) definition of regions of brain dysfunction using 14C-deoxyglucose metabolic labelling; and (c) identification of abnormal neuropathology, AB deposition, neurofibrillary tangle formation, gliosis and neuronal loss, using appropriate immunohistologic and standard histologic methods. We would like to generate the best possible representative murine model of AD by studying disease phenotypes in mice expressing different APP mutations, isoforms, and homologues. We shall use the following transgenes: (a) APP variants containing a variety of mutations associated with familial Alzheimer's disease; (b) APP isoforms containing or lacking the Kunitz-protease-inhibitor; and (c) mutant human and murine/human chimeric APP homologues. In the longterm, if our analyses of the Tg mice we currently have or the ones we plan to create reveal AD or an Alzheimer's-like illness, they may be useful for elucidating the pathogenesis and treatment of AD. The mice would provide a tool for studying mutant APP metabolism and its role in AD, and for examining various proposed mechanisms of pathogenesis, such as amyloidogenesis and Abeta fibrillogenesis, horizontal transmission of disease, oxidation and free-radical production, inflammation, neurotrophic factor deprivation, apolipoprotein E4 metabolism, and potassium channel dysfunction.
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