Central to the pathology of Alzheimer's disease (AD) is the profuse accumulation of amyloid-
(A
) peptides in the brain of affected individuals, and several amyloid precursor protein (APP) transgenic(Tg) mice models have been created to mimic A
deposition. Among these, the PDAPP Tg mice carryingthe familial AD APP 717 Val
Phe mutation have been widely used to test potential AD therapeuticinterventions including active and passive anti-A
immunizations. The structure and biochemistry of thePDAPP Tg mice A
-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 PDAPPmice produce a variety of C-terminally elongated A
peptides in addition to A
n-40 and A
n-42, aswell as N-terminally truncated peptides, suggesting anomalous proteolysis of both APP and A
. Importantalterations in the overall APP degradation also occur in this model, resulting in a striking comparativelack of CT83 and CT99 fragments, which may be inherent to the strain of mice, a generalized
-secretasefailure, or the ultimate manifestation of the overwhelming amount of expressed human transgene; thesealterations are not observed in other strains of APP Tg mice or in sporadic AD. Understanding at themolecular level the nature of these important animal models will permit a better understanding of therapeuticinterventions directed to prevent, delay, or reverse the ravages of sporadic AD.