Amyloid ß-Protein Assembly: Differential Effects of the Protective A2T Mutation and Recessive A2V Familial Alzheimer's Disease Mutation.

Oligomeric states of the amyloid ß-protein (Aß) appear to be causally related to Alzheimer's disease (AD). Recently, two familial mutations in the amyloid precursor protein gene have been described, both resulting in amino acid substitutions at Ala2 (A2) within Aß. An A2V mutation causes autosomal recessive early onset AD. Interestingly, heterozygotes enjoy some protection against development of the disease. An A2T substitution protects against AD and age-related cognitive decline in non-AD patients. Here, we use ion mobility-mass spectrometry (IM-MS) to examine the effects of these mutations on Aß assembly. These studies reveal different assembly pathways for early oligomer formation for each peptide. A2T Aß42 formed dimers, tetramers, and hexamers, but dodecamer formation was inhibited. In contrast, no significant effects on Aß40 assembly were observed. A2V Aß42 also formed dimers, tetramers, and hexamers, but it did not form dodecamers. However, A2V Aß42 formed trimers, unlike A2T or wild-type (wt) Aß42. In addition, the A2V substitution caused Aß40 to oligomerize similar to that of wt Aß42, as evidenced by the formation of dimers, tetramers, hexamers, and dodecamers. In contrast, wt Aß40 formed only dimers and tetramers. These results provide a basis for understanding how these two mutations lead to, or protect against, AD. They also suggest that the Aß N-terminus, in addition to the oft discussed central hydrophobic cluster and C-terminus, can play a key role in controlling disease susceptibility.