Amyloid precursor protein processing and Ab42 deposition in a transgenic mouse model of Alzheimer disease (PDAPP mouseyb-peptideyamyloidogenesis)

The PDAPP transgenic mouse, which over- expresses human amyloid precursor protein (APP717V3F), has been shown to develop much of the pathology associated with Alzheimer disease. In this report, levels of APP and its amyloidogenic metabolites were measured in brain regions of transgenic mice between 4 and 18 months of age. While absolute levels of APP expression likely contribute to the rate of amyloid b-peptide (Ab) deposition, regionally specific factors also seem important, as homozygotic mice express APP levels in pathologically unaffected regions in excess of that measured in certain amyloid plaque-prone regions of heterozygotic mice. Regional levels of APP and APP-b were nearly constant at all ages, while Ablevels dramatically and predictablyincreasedinbrainregionsundergoinghistochem- ically confirmed amyloidosis, most notably in the cortex and hippocampus. In hippocampus, Ab concentrations increase 17-fold between the ages of 4a nd 8m onths, and by 18 months of age are over 500-fold that at 4m onths, reaching an average level in excess of 20 nmol of Ab per g of tissue. Ab1-42 constitutesthevastmajorityofthedepositingAbspecies.The similarities observed between the PDAPP mouse and human AlzheimerdiseasewithregardtoAb42depositionoccurringin a temporally and regionally specific fashion further validate theuseofthemodelinunderstandingprocessesrelatedtothe disease.