Reducing the production of toxic Abeta peptides in Alzheimer's disease by mutating the APP cholesterol-binding site: a new therapeutic strategy?

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Alzheimer's disease (AD) is the most common form of dementia in the elderly population and is characterized by two prominent neuropathological lesions: extracellular amyloid-beta (Abeta) containing plaques and intraneuronal fibrillary tangles comprised of aberrantly hyperphosphorylated tau protein. Current treatments targeting the amyloid pathology have had limited success so far. They aim at either reducing the production of Abeta peptides from the amyloid precursor protein or rely on immunotherapy (active or passive) to neutralize Abeta with antibodies. We previously found that by introducing a specific mutation in the cholesterol binding site of the amyloid precursor protein, we could generate short and non-toxic Abeta peptides. Here we will test i) if this specific mutation produces short and non-toxic Abeta peptides in human neuronal cells and in mouse models and, ii) when added on the top of a familial AD mutation, if it could prevent the production of toxic Abeta peptides due to AD mutation. In addition, we will develop new antibodies against these short Abeta peptides to measure their levels in biological fluids from elderly subjects with or without amyloid pathology in their brain. This project should provide data to consider early preventive treatments producing short and non-toxic Abeta peptides.