Altered APP processing in PDAPP (Va1717→Phe) transgenic mice yields extended-length Aβ peptides

Central to the pathology of Alzheimer's disease (AD) is the profuse accumulation of amyloid-beta (A beta) peptides in the brain of affected individuals, and several amyloid precursor protein (APP) transgenic (Tg) mice models have been created to mimic A beta deposition. Among these, the PDAPP Tg mice carrying, the familial AD APP 717 Val -> Phe mutation have been widely used to test potential AD therapeutic interventions including active and passive anti-A beta immunizations. The structure and biochemistry of the PDAPP Tg mice A beta-related peptides were investigated using acid and detergent lysis of brain tissue, ultracentrifugation, FPLC, HPLC, enzymatic and chemical cleavage of peptides, Western blot, immunoprecipitation, and MALDI-TOF and SELDI-TOF mass spectrometry. Our experiments reveal that PDAPP mice produce a variety of C-terminally elongated A peptides in addition to A beta n-40 and A beta n-42, as well as N-terminally truncated peptides, suggesting anomalous proteolysis of both APP and A. Important alterations in the overall APP degradation also occur in this model, resulting in a striking comparative lack of CT83 and CT99 fragments, which may be inherent to the strain of mice, a generalized gamma-secretase failure, or the ultimate manifestation of the overwhelming amount of expressed human transgene; these alterations are not observed in other strains of APP Tg mice or in sporadic AD. Understanding at the molecular level the nature of these important animal models will pen-nit a better understanding of therapeutic interventions directed to prevent, delay, or reverse the ravages of sporadic AD.