Most Alzheimer’s disease (AD) is sporadic, i.e., not the result of inheritance. Familial AD is relatively quite rare, but by studying heritable AD we’ve learned a disproportionately large amount about the genetic risk factors that predispose an individual to contract the disease.
One of the major risk factors for AD is mutation in the amyloid precursor protein (APP) gene. Mutant APP is more likely to be proteolytically cleaved into the β-amyloid (Aβ) form, which generates the amyloid fibrils and plaques that characterize AD pathology. Production of the toxic protein form is, genetically, speaking, a gain of function — so these APP mutations cause dominant inheritance of familial AD, i.e., a patient only needs one copy of the gene in order to have a very high risk of early-onset AD, and they’re 50% likely to pass this phenotype on to their children.
A newly discovered mutation, however, turns that inheritance pattern on its head. The A673V mutation in APP is associated with AD, but the inheritance pattern is recessive, i.e., a patient needs two mutant alleles in order to acquire the disease risk. In combination with wildtype allele, A673V doesn’t cause AD. Furthermore, the presence of the mutant protein prevents the wildtype protein from forming amyloid fibrils, even under very favorable in vitro conditions. Di Fede et al.:
A Recessive Mutation in the APP Gene with Dominant-Negative Effect on Amyloidogenesis
β-Amyloid precursor protein (APP) mutations cause familial Alzheimer’s disease with nearly complete penetrance. We found an APP mutation [alanine-673valine-673 (A673V)] that causes disease only in the homozygous state, whereas heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced β-amyloid (Aβ) production and formation of amyloid fibrils in vitro. Co-incubation of mutated and wild-type peptides conferred instability on Aβ aggregates and inhibited amyloidogenesis and neurotoxicity. The highly amyloidogenic effect of the A673V mutation in the homozygous state and its anti-amyloidogenic effect in the heterozygous state account for the autosomal recessive pattern of inheritance and have implications for genetic screening and the potential treatment of Alzheimer’s disease.
The basis of this effect is unknown — why would an amyloidogenic peptide fail to form fibrils simply because a non-amyloidogenic peptide is present? It’s tempting to speculate that is has to do with some aspect of the way in which Aβ proteins assemble into oligomers. Crystals form only from assemblies of like objects; by analogy, perhaps there are flavors of APP that can only form oligomers with their own kind — oligomers that are disrupted by the presence of other similar, but non-identical, monomers. At present we’ve got very little information to inform hypothesis building: amyloid fibrils are poor subjects for the standard techniques of structural biology, so their molecular details — and any clue about how this unusual mutant behaves — remain a mystery.
One experiment I’m dying to see: Do the A673V mutant proteins prevent other APP mutant proteins (the ones associated with the dominant form of familial AD) from forming fibrils?