gamma-Secretase activity is associated with Braak Senile Plaque stages.

Amyloid beta-proteins (Abetas) Abeta1-42 and Abeta1-43 are converted via two product lines of gamma-secretase to Abeta1-38 and Abeta1-40. This parallel stepwise processing model of gamma-secretase predicts that Abeta1-42 and Abeta1-43, and Abeta1-38 and Abeta1-40 are proportional to each other, respectively. To obtain further insight into the mechanisms of parenchymal Abeta deposition, these four Abeta species were quantified in insoluble fractions of human brains (Brodmann areas 9-11) at various Braak senile plaque (SP) stages, using specific enzyme-linked immunosorbent assays. With advancing SP stages, the amounts of deposited Abeta1-43 in the brain increased proportionally to those of Abeta1-42. Similarly, the amounts of deposited Abeta1-38 correlated with those of Abeta1-40. Surprisingly, the ratios of deposited Abeta1-38/Abeta1-42 and Abeta1-40/Abeta1-43 were proportional and discriminated the Braak SP stages accurately. This result indicates that the generation of Abeta1-38 and Abeta1-40 decreased and the generation of Abeta1-42 and Abeta1-43 increased with advancing SP stages. Thus, Abetas deposition might depend on gamma-secretase activity, as it does in the cerebrospinal fluid (CSF). Here, the extracted gamma-secretase from Alzheimer's disease (AD) brains generates amount of Abeta1-42 and Abeta1-43 compared with cognitively normal brains. This refractory gamma-secretase localized in detergent-solubilized fractions from brain cortices. But activity modulated gamma-secretase, which decreases Abeta1-42 and Abeta1-43 in the CSF, localized in detergent-insoluble fractions. These gamma-secretase drastic alterations reflect Abeta situation in AD brains.