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

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.

Alzheimer's disease (AD) is the most common form of dementia in the elderly population and is characterized by two prominent pathologies, extracellular amyloid-beta (Abeta) containing plaques and intraneuronal fibrillary tangles comprised of aberrantly hyperphosphorylated tau protein. Abeta peptides of various lengths are produced by sequential proteolysis of the transmembrane amyloid precursor protein (APP) by the beta- and the gamma-secretase both of which operate in the membrane bilayer containing cholesterol. We previously found that K to A mutation in the cholesterol-binding site of APP at position 28 in the Abeta sequence produces short and non-toxic Abeta peptides (mainly Abeta33). Here we will develop new human neuroblastoma and iPSC-derived neurons, and mouse models, with the K28A +/- familial AD London mutation to test if the K28A mutation is protective against toxic Abeta peptides and if producing short Abeta peptides throughout life starting at first embryonic stages is viable in mice. We will develop new anti-Abeta33 antibodies to measure Abeta33 levels in biological fluids from elderly subjects with or without amyloid pathology in their brain, possibly associated to lower brain cholesterol levels. This project should stimulate the search for new preventive treatments producing short Abeta peptides.