It is widely accepted that Abeta peptides, the principal component of senile plaques, play a causative role in the pathogenesis of Alzheimer’s disease (AD). Abeta is derived from larger beta-amyloid precursor proteins (APP). Early-onset, familial AD (FAD) is caused by inheritance of mutations in genes encoding APP or presenilin (PS1 or PS2) variants. Mutations in APP lead to the production of elevated levels of Abeta or the ratio of Abeta42/40 peptides. Importantly, all of the known APP mutations reside proximal to, or within, the Abeta peptide sequence. Very recently, Rudy Tanzi and colleagues (unpublished) have identified additional mutations in APP that co-segregate with two early-onset FAD pedigrees, but surprisingly, these mutations are quite a distance from the Abeta sequence. The mechanism(s) by which these novel variants influence Abeta production and/or deposition is not known, but our current proposal seeks to clarify these important issues in cell culture and transgenic mouse models.
In Vitro and In Vivo Analysis of APP Variants
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