Good gene, bad gene: New APP variant may be both

APP mutations cause Alzheimer disease (AD) with virtually complete penetrance. We found a novel APP mutation (A673V) in the homozygous state in a patient with early-onset AD-type dementia and in his younger sister showing initial signs of cognitive decline. It is noteworthy that the heterozygous relatives were not affected, suggesting that this mutation is inherited as an autosomal recessive trait. Studies on molecular events for the recessive mutation in causing disease revealed a double synergistic effect: the A673V APP variant shifts APP processing towards the amyloidogenic pathway with increased production of Aβ peptides and it markedly enhances the aggregation and fibrillogenic properties of both Aβ1–40 and Aβ1–42. However, co-incubation of mutated and wild-type (wt) Aβ species resulted in inhibition of amyloidogenesis, consistent with the observation that heterozygous carriers do not develop the disease. The opposite effects of the A673V mutation in the homozygous and heterozygous state on amyloidogenesis account for the autosomal recessive pattern of inheritance, revealing a new scenario in AD genetics and pathogenesis. The anti-amyloidogenic properties of this novel human Aβ variant may offer grounds for the development of therapeutic strategies for AD based on modified Aβ peptides. Indeed, the interaction between mutated Aβ1–6 and wt full-length Aβ prevents amyloid fibril formation. The anti-amyloidogenic effect is further amplified by the use of a mutated six-mer peptide, constructed entirely from D-amino acids to increase the its stability in vivo. Here we reviewed the studies on pathogenic mechanisms associated with the A673V mutation and the first experimental steps toward the development of a novel disease-modifying therapy for AD.

► A673V APP is the first AD-associated mutation with autosomal recessive inheritance.
► In the homozygous state the A673V mutation boosts amyloidogenesis and Aβ neurotoxicity.
► In the heterozygous state it hinders amyloidogenesis preventing the occurrence of AD.
► A disease-modifying therapy for AD is proposed using Aβ peptides carrying the A2V mutation.