Lack of beta-amyloidosis in transgenic mice expressing low levels of familial Alzheimer's disease missense mutations.
Point mutations within the beta-amyloid precusor protein (beta-APP) gene known to segregate with Alzheimer's disease in certain families were introduced into human beta-APP cDNAs and expressed under the control of a neuron-specific enolase (NSE) promoter in mice. The transgenic animals exhibited transgene expression predominantly in neocortex and hippocampus where the levels were maximally 1.3-fold of those of wild-type mouse beta-APP. Quantitative immunoblot analysis in homozygous mice carrying different missense mutations showed slightly increased alpha-secretory processing. In V7171 mice compared to nontransgenic mice there was more alpha-secretory beta-APP (beta-APPsec) in cortex/hippocampus, less in cerebellum, and no difference in midbrain/brain stem. In none of the transgenic animals tested was a 4 kDa amyloid fragment detected by Western blotting of brain extracts, immunohistochemistry, or by 125I-A beta-binding onto brain sections. No glial reaction was observed. Behavioral analysis of mice carrying the V7171 mutation showed no appreciable deficit in comparison to wild-type mice. Together, these data suggest that low levels of expression of mutated beta-APP in 10-12-month-old transgenic mouse brains result in slightly more beta-APPsec, and are insufficient to induce amyloidogenic processing and AD-like pathology.
Malherbe
P
P
Pharma Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Richards
J G
JG
Martin
J R
JR
Bluethmann
H
H
Maggio
J
J
Huber
G
G
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics; D000686:Amyloidosis / Q000235:genetics* / Q000473:pathology* / Q000523:psychology; D000818:Animals; D001483:Base Sequence; D001522:Behavior, Animal / Q000502:physiology; D015139:Blotting, Southern; D015153:Blotting, Western; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010751:Phosphopyruvate Hydratase / Q000235:genetics; D017354:Point Mutation / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D019076:Transgenes / Q000235:genetics
D016229:Amyloid beta-Peptides; D012333:RNA, Messenger; D010751:Phosphopyruvate Hydratase