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The beta-amyloid protein in Alzheimer's disease: A study of alpha, beta, and gamma cleavages

Cheung, Tobun Toby
http://rave.ohiolink.edu/etdc/view?acc_num=case1061918493

Abstract Details

1994, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
The 39-43 residue amyloid β protein (Aβ ) deposited as amyloid in Alzheimer's disease (AD) is derived from a large amyloid β protein precursor (β APP). Normal β APP processing produces ∼8.7, ∼9.6, ∼10.9, and ∼11.4 kD COOH-terminal fragments (CTFs). In this study, I metabolically labeled cells with 3H-phenylalanine plus 35S-methionine and radiosequenced immunoprecipitated CTFs. My analysis confirmed that the ∼8.7 kD CTF begins at Aβ17 and showed that the ∼9.6 and ∼10.9 kD CTFs begin at Aβ10 and Aβ4 respectively. Significantly, I found that the 11.4 kD CTF begins at Aβ1. Thus normal β APP processing produces a potentially amyloidogenic CTF that has Aβ intact at its NH2 terminus. To determine whether Aβ can be released from this CTF, a model Aβ-bearing CTF was expressed in transfected cells. These cells released a soluble 4 kD protein shown by sequencing to be Aβ . Transfected cells expressing full length βAPP also released a 4 kD protein shown by radiosequencing to be authentic Aβ , and Aβ was detected in human cerebrospinal fluid. Collect ively, these findings established that cells normally secrete 4 kD Aβ . Studies of β APPs known to cause familial AD (FAD) had shown that the β APPΔ NL (Swedish) mutant produces excess 11.4 kD CTF and secretes excess Aβ. By radiosequencing, I showed that the Δ NL mutant is cleaved at the same location as wild type β APP producing an 11.4 kD CTF and Aβ that both begin at Aβ1. Thus the Δ NL mutation appears to accelerate a cleavage that releases an 11.4 kD CTF identical to that normally produced from wild type β APP, and it appears that this CTF is further processed to release excess Aβ . Finally, I showed that cells expressing the FAD-linked β APP717 (London) mutants secrete excess Aβ1-42,43, a peptide that very rapidly forms amyloid fibrils. Collectively, these observations that the known FAD-linked β APP mutations all alter processing in a way that foster amyloid deposition, provide strong evidence that amyloid deposition is an essential element in the development of AD
Steven Younkin (Advisor)
131 p.
Biology, Cell
Alzheimer's disease; Beta-amyloid protein

Recommended Citations

Citations

  • Cheung, T. T. (1994). The beta-amyloid protein in Alzheimer's disease: A study of alpha, beta, and gamma cleavages [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1061918493

    APA Style (7th edition)

  • Cheung, Tobun. The beta-amyloid protein in Alzheimer's disease: A study of alpha, beta, and gamma cleavages. 1994. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1061918493.

    MLA Style (8th edition)

  • Cheung, Tobun. "The beta-amyloid protein in Alzheimer's disease: A study of alpha, beta, and gamma cleavages." Doctoral dissertation, Case Western Reserve University, 1994. http://rave.ohiolink.edu/etdc/view?acc_num=case1061918493

    Chicago Manual of Style (17th edition)

case1061918493
558
© 1994, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.
Release 3.2.12