Amyloid beta protein (A beta) deposition: A beta 42(43) precedes A beta 40 in Down syndrome

The chronological relationship regarding deposition of amyloid beta protein (A beta) species, A beta 40 and A beta 42(43), was investigated in 16 brains from Down syndrome patients aged 31 to 64 years. The frontal cortex was probed with two end-specific monoclonals that recognize A beta 40 or A beta 42(43). All senile plaques detected with an authentic beta monoclonal were also A beta 42(43) positive, but only a varying proportion was A beta 40 positive. In young (< or = 50 years old) brains there were many A beta 42(43)-positive, A beta 40-negative diffuse plaques, but only few A beta 40-positive senile plaques (mean, 6.3% of total number of senile plaques). The 2 youngest Down syndrome brains showed only diffuse plaques that were all A beta 42(43) positive but A beta 40 negative. Old (> 50 years old) brains contained many mature senile plaques with amyloid cores in addition to diffuse and immature plaques and the proportion of A beta 40-positive senile plaques was increased (mean, 42% of total). Cerebral amyloid angiopathy was more abundant in old Down syndrome brains and was positive for both A beta 40 and A beta 42(43). In cerebral amyloid angiopathy, A beta 40 predominated over A beta 42(43) in both staining intensity and number of positive vessels. These results indicate that (1) the A beta species initially deposited in the brain as senile plaques is A beta 42(43) and A beta 40 only appears a decade later, and (2) in cerebral amyloid angiopathy A beta 40 appears as early as A beta 42(43).