Brain regional correlation of amyloid-β with synapses and apolipoprotein E in non-demented individuals: potential mechanisms underlying regional vulnerability to amyloid-β accumulation

To reveal the underlying mechanisms responsible for the regional vulnerability to amyloid-beta (A beta) accumulation prior to the development of Alzheimer's disease, we studied distribution of A beta, apolipoprotein E (apoE), synaptic markers, and other molecules involved in A beta metabolism in multiple brain areas of non-demented individuals. Twelve brain regions including neocortical, limbic, and subcortical areas were dissected from brains of non-demented individuals and extracted according to increasing insolubility by a sequential three-step method. The levels of A beta 40, A beta 42, apoE, APP, APP-CTF beta, BACE1, presenilin-1, neprilysin, insulysin, LRP1, LDLR, synaptophysin, PSD95, GFAP, and lactate were determined by ELISAs or enzymatic assays. The regional distribution of apoE showed moderate-to-strong inverse correlation with levels of A beta, especially insoluble A beta 40. On the other hand, the regional distributions of synaptic markers, particularly PSD95, showed moderate-to-strong positive correlation with levels of A beta, especially soluble A beta 40. The regional correlations between A beta and LRP1, GFAP, or lactate were mild-to-moderate. Moderate-to-strong positive regional correlations were observed between apoE and GFAP or lactate and between PSD95 and LRP1. No significant regional correlations were detected between A beta and APP, APP-CTF beta, BACE1, or presenilin-1, those involved in A beta production. There were no significant negative regional correlations between A beta and two major A beta degrading enzymes, neprilysin and insulysin. These regional correlations remained consistent regardless of the degree of A beta accumulation. The regional vulnerability to A beta accumulation may be due to a net balance between two competing processes: (1) synapses involved in promoting the initial A beta accumulation and (2) astrocyte-derived apoE involved in preventing A beta accumulation.