Altered APP processing in PDAPP (Val717 → Phe) transgenic mice yields extended-length Aβ peptides

Chera Esh, Lyle Patton, Walter Kalback, Tyler A. Kokjohn, John Lopez, Daniel Brune, Amanda J. Newell, Thomas Beach, Dale Schenk, Dora Games, Steven Paul, Kelly Bales, Bernardino Ghetti, Eduardo M. Castaño, Alex E. Roher

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Central to the pathology of Alzheimer's disease (AD) is the profuse accumulation of amyloid-β (Aβ) peptides in the brain of affected individuals, and several amyloid precursor protein (APP) transgenic (Tg) mice models have been created to mimic Aβ 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-Aβ immunizations. The structure and biochemistry of the PDAPP Tg mice Aβ-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 Aβ peptides in addition to Aβ n-40 and Aβ n-42, as well as N-terminally truncated peptides, suggesting anomalous proteolysis of both APP and Aβ. 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 γ-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 permit a better understanding of therapeutic interventions directed to prevent, delay, or reverse the ravages of sporadic AD.

Original languageEnglish (US)
Pages (from-to)13807-13819
Number of pages13
JournalBiochemistry
Volume44
Issue number42
DOIs
StatePublished - Oct 25 2005

ASJC Scopus subject areas

  • Biochemistry

Fingerprint Dive into the research topics of 'Altered APP processing in PDAPP (Val717 → Phe) transgenic mice yields extended-length Aβ peptides'. Together they form a unique fingerprint.

  • Cite this

    Esh, C., Patton, L., Kalback, W., Kokjohn, T. A., Lopez, J., Brune, D., Newell, A. J., Beach, T., Schenk, D., Games, D., Paul, S., Bales, K., Ghetti, B., Castaño, E. M., & Roher, A. E. (2005). Altered APP processing in PDAPP (Val717 → Phe) transgenic mice yields extended-length Aβ peptides. Biochemistry, 44(42), 13807-13819. https://doi.org/10.1021/bi051213+