AGING RENDERS THE BRAIN VULNERABLE TO AMYLOID BETA-PROTEIN NEUROTOXICITY

The formation of fibrillar deposits of amyloid beta protein (A beta) i n 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 neu rodegenerative process in AD (refs. 3,4). The involvement of A beta in the neurodegenerative process is suggested by the neurotoxicity of th e fibrillar form of A beta in vitro(5-11). However, mice transgenic fo r the A beta precursor protein that develop amyloid deposits in the br ain do not show the degree of neuronal loss or tau phosphorylation fou nd in AD (refs. 12-16). Here we show that microinjection of plaque-equ ivalent concentrations of fibrillar, but not soluble, A beta in the ag ed rhesus monkey cerebral cortex results in profound neuronal loss, ta u phosphorylation and microglial proliferation. Fibrillar A beta at pl aque-equivalent concentrations is not toxic in the young adult rhesus brain. A beta toxicity in vivo is also highly species-specific; toxici ty is greater in aged rhesus monkeys than in aged marmoset monkeys, an d is not significant in aged rats. These results suggest that AB neuro toxicity in vivo is a pathological response of the aging brain, which is most pronounced in higher order primates. Thus, longevity may contr ibute to the unique susceptibility of humans to Alzheimer's disease by rendering the brain vulnerable to A beta neurotoxicity.