REGIONAL DISTRIBUTION OF AMYLOID-BETA, SOLUBLE APP AND SYNAPTIC MARKERS IN HUMAN BRAINS

Abstract

We recently reported the strong regional association between postsynaptic markers and Abeta accumulation in human brains, suggesting that synapses play important roles in Abeta accumulation (Shinohara et al., Acta Neuropathologica 2013;125(4):535-547). To further reveal potential mechanism underlying the involvement of synapses in Abeta accumulation, we determined the regional distribution of soluble APPalpha and APPbeta by specific ELISAs and addressed their association with the regional distribution of Abeta, synaptic markers and other related molecules. Twelve brain regions including neocortical, limbic and subcortical areas were dissected from brains of non-demented individuals with or without Abeta accumulation (n = 27, age = 89.7 ± 9.4 years) and sporadic Alzheimer’s disease (AD) patients (n=19, age = 84.7 ± 7.8 years) extracted according to increasing insolubility by a sequential three-step method (TBS, Triton-X and guanidine). The levels of Abeta40, Abeta42, sAPPalpha, sAPPbeta, APP, BACE1, PSD95, synaptophysin, LRP1 were determined by ELISAs. In non-demented individuals, the regional distribution of sAPPalpha and sAPPbeta correlated with one another, while their correlation with full-length APP was weak. Importantly, the correlations between insoluble Abeta (especially Abeta42) and sAPPalpha or sAPPbeta were strong. Moreover, the postsynaptic marker PSD95 showed strong regional correlation with sAPPalpha and sAPPbeta. No significant association was observed between BACE1 and sAPPbeta. The distribution of sAPPalpha and sAPPbeta also showed strong regional association with Abeta accumulation in AD patients. These results suggest a potential involvement of synaptic function in the metabolism of soluble APP, associated with the accumulation of Abeta during the development of sporadic Alzheimer’s disease. We are currently addressing how synapses regulate the metabolism of soluble APP by in vivo microdialysis or another experimental system.