Vicious cycle in Alzheimer's disease: Amyloid beta aggravates its own production

Gradual changes in the steady-state levels of amyloid beta (Aβ) in the brain of Alzheimer's disease (AD) patients are thought to initiate the amyloid cascade. Herein, we tested the impact of oligomeric Aβ (oligoAβ) on the cleavage of APP using neuronal and non-neuronal cells. Low micromolar concentrations of oligoAβ significantly decreased the membrane fluidity in the living cells, which was accompanied by an elevated production of endogenous Aβ. Accordingly, APP CTF-fragment C99 levels was significantly increased, indicating an enhanced β-secretase cleavage. Using compounds that manipulate membrane properties, we showed that the membrane fluidity determines the ectodomain shedding of APP, regardless of the mode of membrane manipulation, e.g. independent of cholesterol levels. Using fluorescently-labelled oligoAβ, we identified GM-1 ganglioside to be the most probable target molecule for Aβ in the cellular membranes of intact cells. To further evaluate Aβ′ s effects on the ectodomain shedding of APP, cells were treated with the β-secretase inhibitor, DAPT. The cellular Aβ production was abolished, the membrane fluidity was normalized and the levels of APPsα were increased by inhibition of β-secretase. Based on the novel findings presented herein, we hypothesise that oligoAβ interacts with the neuronal membranes by binding to GM-1 ganglioside and accelerate the intra-membranous proteolytic cleavage of APP, thus in a vicious cycle endogenous Aβ triggers its own production.