Perry, Robert H

Publication Detail

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Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice.

B T Lamb; L M Call; H H Slunt; K A Bardel; A M Lawler; C B Eckman; S G Younkin; G Holtz; S L Wagner; D L Price; et al. (Profiled Authors: Price, Donald L; Younkin, Steven G; Eckman, Christopher B; Sisodia, Sangram S)

Department of Genetics, Case Western Reserve University, Cleveland, OH 44106, USA. btl@po.cwru.edu
Human molecular genetics 1997;6(9):1535-41.

Missense mutations in the beta-amyloid precursor protein gene (APP) co-segregate with a small subset of autosomal dominant familial Alzheimer's disease (FAD) cases wherein deposition of the 39-43 amino acid beta-amyloid (A beta) peptide and neurodegeneration are principal neuropathological hallmarks. To accurately examine the effect of missense mutations on APP metabolism and A beta production in vivo, we have introduced yeast artificial chromosomes (YACs) containing the entire approximately 400 kbp human APP gene encoding APP harboring either the asparagine for lysine and leucine for methionine FAD substitution at codons 670 and 671 (APP(K670N/M671L)), the isoleucine for valine FAD substitution at codon 717 (APP(V7171)) or a combination of both substitutions into transgenic mice. We demonstrate that, relative to YAC transgenic mice expressing wild-type APP, high levels of A beta peptides are detected in the brains of YAC transgenic mice expressing human APP(K670N/M671L) that is associated with a concomitant diminution in the levels of apha-secretase-generated soluble APP derivatives. Moreover, the levels of longer A beta peptides (species terminating at amino acids 42/43) are elevated in YAC transgenic mice expressing human APP(V7171). These mice should prove valuable for detailed analysis of the in vivo effects of the APP FAD mutations in a variety of tissues and throughout aging and for testing therapeutic agents that specifically alter APP metabolism and A beta production.

4 Originating Grant

• 1.

  Price, Donald L

  Alzheimer's Disease and Animal Models

  15 July 1997 - 31 March 2010

  NATIONAL INSTITUTE ON AGING

  Total Funding: $ 44,095,695

• 2.

  ALBERT, MARILYN B

  Johns Hopkins Alzheimer's Disease Research Center

  15 July 1997 - 31 March 2015

  NATIONAL INSTITUTE ON AGING

  Total Funding: $ 5,559,946

• 3.

  PRICE, DONALD L

  DISORDERS OF AGING--TRANSMITTER SYSTEMS & NEUROTROPHINS

  1 April 1984 - 30 June 1997

  NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

  Total Funding: $ 10,370,755

• 4.

  PRICE, DONALD L

  THE FOREBRAIN CHOLINERGIC SYSTEM IN HEALTH AND DISEASE

  1 April 1984 - 30 June 1992

  NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

  Total Funding: $ 4,029,351

Scientific Context

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