Genetic and pharmacological evidence of intraneuronal Aβ accumulation in APP transgenic mice

Intraneuronal punctate immunostaining in Alzheimer's disease brain and amyloid-beta precursor protein (APP) transgenic mice has been suggested to represent A beta, but this is somewhat controversial. Here we show that both biochemical A beta levels and intraneuronal immunostaining are reduced in APP transgenic mice when gamma-secretase is inhibited. Moreover, BACE-1 deficient APP transgenic mice show neither A beta production nor intraneuronal immunostaining. Our findings suggest that the punctate immunostaining with APP antibodies is due to A beta that has accumulated inside neurons. Similar type of intraneuronal A beta accumulation, which precedes senile plaque formation, may link A beta to tauopathy and neurodegeneration in Alzheimer's disease pathogenesis. (C) 2009 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.