γ-Secretase Activity Is Associated with Braak Senile Plaque Stages

Amyloid beta-proteins (A beta s) A beta 1-42 and A beta 1-43 are converted via two product lines of gamma-secretase to A beta 1-38 and A beta 1-40. This parallel stepwise processing model of gamma-secretase predicts that A beta 1-42 and A beta 1-43, and A beta 1-38 and A beta 1-40 are proportional to each other, respectively. To obtain further insight into the mechanisms of parenchymal A beta deposition, these four A beta species were quantified in insoluble fractions of human brains (Brodmann areas 9 to 11) at various Braak senile plaque (SP) stages, using specific enzyme-linked immunosorbent assays. With advancing SP stages, the amounts of deposited A beta 1-43 in the brain increased proportionally to those of A beta 1-42. Similarly, the amounts of deposited A beta 1-38 correlated with those of A beta 1-40. Surprisingly, the ratios of deposited A beta 1-38/A beta 1-42 and A beta 1-40/A beta 1-43 were proportional and discriminated the Braak SP stages accurately. This result indicates that the generation of A beta 1-38 and A beta 1-40 decreased and the generation of A beta 1-42 and A beta 1-43 increased with advancing SP stages. Thus, A beta s deposition might depend on gamma-secretase activity, as it does in the cerebrospinal fluid. Here, the extracted gamma-secretase from Alzheimer disease brains generates an amount of A beta 1-42 and A beta 1-43 compared with cognitively normal brains. This refractory gamma-secretase localized in detergent-solubilized fractions from brain cortices. But activity modulated gamma-secretase, which decreases A beta 1-42 and A beta 1-43 in the cerebrospinal fluid, localized in detergent-insoluble fractions. These drastic alterations reflect A beta situation in Alzheimer disease brains.