Fig. 8

A proposed mechanism for the recessive heredity of the Osaka mutation. The Osaka mutation has dual effects; a loss-of-function of APP leading to GABAergic depletion and gain-of-toxic-function of Aβ to accelerate its oligomerization. While the former effect accounts for the recessive inheritance of this mutation, the latter seems to be a dominant effect to cause dementia even in heterozygotes. But practically, Aβ oligomer accumulation is not detected until GABAergic depletion proceeds. This is probably because Aβ production is negatively regulated by GABAergic inhibitory input. Once Aβ oligomers accumulate, it triggers pathological cascade of AD, including abnormal tau phosphorylation, synapse loss, glial activation, and eventual neuron loss