Staging of cytoskeletal and beta-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer's disease

We have examined the relationships between dementia, loss of synaptic prote ins, changes in the cytoskeleton, and deposition of beta-amyloid plaques in the neocortex in a clinicopathologically staged epidemiological cohort usi ng a combination of biochemical and morphometric techniques. We report that loss of synaptic proteins is a late-stage phenomenon, occurring only at Br aak stages 5 and 6, or at moderate to severe clinical grades of dementia, L oss of synaptic proteins was seen only after the emergence of the full spec trum of tau and beta-amyloid pathology in the neocortex at stage 4, but not in the presence of beta-amyloid plaques alone. Contrary to previous studie s, we report increases in the levels of synaptophysin, syntaxin, and SNAP-2 5 at stage 3 and of alpha-synuclein and MAP2 at stage 4, Minimal and mild c linical grades of dementia were associated with either unchanged or elevate d levels of synaptic proteins in the neocortex, Progressive aggregation of paired helical filament (PHF)-tau protein could be detected biochemically f rom stage 2 onwards, and this was earliest change relative to the normal ag ing background defined by Braak stage 1 that we were able to detect in the neocortex. These results are consistent with the possibility that failure o f axonal transport associated with early aggregation of tau protein elicits a transient adaptive synaptic response to partial de-afferentation that ma y be mediated by trophic factors. This early abnormality in cytoskeletal fu nction may contribute directly to the earliest clinically detectable stages of dementia.