Genetic and pharmacological evidence of intraneuronal Abeta 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 Abeta, but this is somewhat controversial. Here we show that both biochemical Abeta levels and intraneuronal immunostaining are reduced in APP transgenic mice when gamma-secretase is inhibited. Moreover, BACE-1 deficient APP transgenic mice show neither Abeta production nor intraneuronal immunostaining. Our findings suggest that the punctate immunostaining with APP antibodies is due to Abeta that has accumulated inside neurons. Similar type of intraneuronal Abeta accumulation, which precedes senile plaque formation, may link Abeta to tauopathy and neurodegeneration in Alzheimer's disease pathogenesis.
Philipson
Ola
O
Department of Public Health and Caring Sciences, Uppsala University, SE-751 85 Uppsala, Sweden.
Lannfelt
Lars
L
Nilsson
Lars N G
LN
D000544:Alzheimer Disease / Q000209:etiology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000032:analysis*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000737:chemistry / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse