Altered APP Processing in PDAPP (Val717 Phe) Transgenic Mice Yields Extended-Length A
详细信息 查看全文
详细信息 查看全文
- 作者：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. Cas
- 刊名：Biochemistry
- 出版年：2005
- 出版时间：October 25, 2005
- 年：2005
- 卷：44
- 期：42
- 页码：13807 - 13819
- 全文大小：345K
- 年卷期：v.44,no.42(October 25, 2005)
- ISSN：1520-4995
文摘
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.
(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.