Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain

Citation
D. Moechars et al., Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain, J BIOL CHEM, 274(10), 1999, pp. 6483-6492
Citations number
38
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
274
Issue
10
Year of publication
1999
Pages
6483 - 6492
Database
ISI
SICI code
0021-9258(19990305)274:10<6483:EPCITM>2.0.ZU;2-1
Abstract
Transgenic mice overexpressing different forms of amyloid precursor protein (APP), i.e. wild type or clinical mutants, displayed an essentially compar able early phenotype in terms of behavior, differential glutamatergic respo nses, deficits in maintenance of long term potentiation, and premature deat h. The cognitive impairment, demonstrated in F1 hybrids of the different AP P transgenic lines, was significantly different from nontransgenic litterma tes as early as 3 months of age. Biochemical analysis of secreted and membr ane-bound APP, C-terminal "stubs," and A beta(40) and A beta(42) peptides i n brain indicated that no single intermediate can be responsible for the co mplex of phenotypic dysfunctions. As expected, the A beta(42) levels were m ost prominent in APP/London transgenic mice and correlated directly with th e formation of amyloid plaques in older mice of this line, Plaques were ass ociated with immunoreactivity for hyperphosphorylated tau, eventually signa ling some form of tau pathology. In conclusion, the different APP transgeni c mouse lines studied display cognitive deficits and phenotypic traits earl y in life that dissociated in time from the formation of amyloid plaques an d will be good models for both early and late neuropathological and clinica l aspects of Alzheimer's disease.