Amyloid-beta precursor protein Swedish mutant allele (APPswe) (APPswe)

The Amyloid-beta precursor protein Swedish mutant allele (APPswe) is a pathogenic genetic variant characterized by a double mutation (Lys670Asn and Met671Leu) in the APP gene (Mullan et al., 1992). This mutation is strategically located at the N-terminus of the amyloid-beta (A-beta) sequence, which serves as the primary cleavage site for the beta-secretase enzyme, BACE1. The Swedish mutation significantly increases the affinity of the APP substrate for BACE1, leading to a dramatic rise in the production of neurotoxic A-beta peptides, particularly A-beta-42 (Haass et al., 1995). As a therapeutic target, APPswe is a prime candidate for precision medicine approaches such as allele-specific RNA interference (RNAi) or CRISPR/Cas9-mediated gene disruption (Miller et al., 2003). These strategies aim to selectively eliminate the expression of the toxic mutant protein while preserving the expression of the wild-type APP allele, which is essential for normal neuronal functions like synaptic plasticity and axonal transport. Current therapeutic development focuses on improving the delivery of these genetic tools to the brain and ensuring high specificity to avoid detrimental off-target effects on the healthy allele.

Other names

APP Swedish mutationKM670/671NL mutationSwedish APPp.Lys670Asn/p.Met671LeuAmyloid beta A4 protein Swedish mutant

Allele-specific silencing of the mutant transcript or gene disruption to reduce the production of neurotoxic amyloid-beta peptides (Miller et al., 2003).