Aging renders the brain vulnerable to amyloid β-protein neurotoxicity

The formation of fibrillar deposits of amyloid beta protein (A beta) in the brain is a pathological hallmark of Alzheimer's disease(1.2) (AD). A central question is whether A beta plays a direct role in the neurodegenerative process in AD (refs. 3,4). The involvement of A beta in the neurodegenerative process is suggested by the neurotoxicity of the fibrillar form of A beta in vitro(5-11). However, mice transgenic for the A beta precursor protein that develop amyloid deposits in the brain do not show the degree of neuronal loss or tau phosphorylation found in AD (refs. 12-16). Here we show that microinjection of plaque-equivalent concentrations of fibrillar, but not soluble, A beta in the aged rhesus monkey cerebral cortex results in profound neuronal loss, tau phosphorylation and microglial proliferation. Fibrillar A beta at plaque-equivalent concentrations is not toxic in the young adult rhesus brain. A beta toxicity in vivo is also highly species-specific; toxicity is greater in aged rhesus monkeys than in aged marmoset monkeys, and is not significant in aged rats. These results suggest that AB neurotoxicity in vivo is a pathological response of the aging brain, which is most pronounced in higher order primates. Thus, longevity may contribute to the unique susceptibility of humans to Alzheimer's disease by rendering the brain vulnerable to A beta neurotoxicity.