Drug Discovery Opinion

Conventional wisdom, supported by in vitro experiments, has previously suggested that phosphoinositide 3-kinase (PI3K) plays a protective role in Alzheimer’s disease. However, a team led by researchers at Cold Spring Harbor has now implicated PI3K in the pathogenesis of the disorder.

The team used fruit-flies (Drosophila) that were engineered to produce human β-amyloid in their brains – a model that mimics many of the features of Alzheimer’s, including age-dependent memory loss, neurodegeneration, β-amyloid deposits and plaque formation. In the model, the presence of β-amyloid enhances long term depression (LTD), a process in which nerve signal transmission at particular synapses is depressed for an extended period. The research demonstrated that the enhanced LTD was a consequence of increased PI3K activity and could be abrogated by genetic silencing or pharmacological inhibition of PI3K.

PI3K inhibition restored LTD to a normal level, rescued β-amyloid peptide (Aβ)-induced memory loss and reduced β-amyloid deposits in the Drosophila brain. The data suggest that Aβ42 stimulates PI3K, which in turn causes memory loss in association with increased accumulation of Aβ42 aggregates.

The researchers note that the up-regulation of PI3K may also explain the insulin-resistance observed in the brains of Alzheimer’s victims. Insulin is one of the molecules that normally induce PI3K activity, which in turn mediates the cell’s response to insulin. Since PI3K is already hyperactivated in response to β-amyloid, it may no longer be able to respond to insulin.

The study is published in PNAS.

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