Researchers may have solved one mystery in the development of familial Alzheimer’s disease (FAD), a genetic variant of the disease that affects a small fraction of the Alzheimer’s population. In a paper published in Nature Communications, a team from Rensselaer Polytechnic Institute follows the trail of two genetic mutations—V44M and V44A—known to cause FAD, and shows how the mutations lead to biochemical changes long linked to the disease.
The hallmark of FAD is the accumulation of the Amyloid Beta 42 peptide in unusually high concentrations within the brain. In a healthy brain, Amyloid Beta-42 (Aß42) and a similar peptide, Amyloid Beta-40 (Aß40), are found in a ratio of about one to nine. In a brain affected by FAD, this ratio is much higher. The two peptides are nearly identical: Aß40 is a chain of 40 amino acids in length; Aß42 is 42 amino acids in length. However, Aß42 is much more toxic to neurons and plays a critical role in memory failure.
Hundreds of known genetic mutations are linked to FAD. They are all related to the processing of a large protein, the amyloid precursor protein (APP), which starts its life partially embedded in the cell membrane of brain cells, and is later cut into several pieces, one of which becomes either Aß42 or Aß40.
In a multi-step process, enzymes make several cuts to APP, and the location of the cuts dictates whether a resulting snippet of APP becomes Aß42 or Aß40. If an enzyme, γ-secretase, makes an initial cut at an amino acid within APP called Threonine 48 (T48), the remaining cuts result in Aß42, whereas if the first cut is made at amino acid Leucine 49, the process will result in Aß40. Read the study abstract.
