Understanding a protein's role in familial Alzheimer's disease

Genetic engineering of human induced pluripotent stem cells has revealed very specifically how a key mutated protein is involved in familial Alzheimer's. Familial Alzheimer’s is a subset of early-onset Alzheimer's disease that is caused by inherited gene mutations.

The study looked at presenilin 1 (PS1), a protein that catalyzes gamma-secretase, an enzyme that splits amyloid precursor protein (APP), creating amyloid-beta. About 20% of the time, these cuts result in potentially harmful amyloid-beta fragments. What this study has found is that mutations in PS1 double the frequency of these bad cuts. Such PS1 mutations are the most common cause of familial Alzheimer’s disease.

http://www.eurekalert.org/pub_releases/2013-11/uoc--uap111413.php

[3620] Woodruff, G., Young J. E., Martinez F. J., Buen F., Gore A., Kinaga J., et al.
(2013).  The Presenilin-1 ΔE9 Mutation Results in Reduced γ-Secretase Activity, but Not Total Loss of PS1 Function, in Isogenic Human Stem Cells.
Cell Reports. 5(4), 974 - 985.

Rare genomic mutations linked to familial Alzheimer's

Mutations in three genes – amyloid precursor protein (APP) and presenilins 1 and 2 – account for around half of all cases of early-onset familial Alzheimer's. A new study has now implicated 10 copy-number variants (duplications or deletions creating a change in the number of copies of a gene), which were found in affected members of 10 families with early-onset Alzheimer's. Notably, different genomic changes were identified in each family.

Genetic data from 261 families with at least one member who developed Alzheimer's before the age of 65 found that two families had CNVs that included the well-established APP gene, but 10 others had CNVs not previously associated with Alzheimer's (although two, CHMP2B and MAPT, have been associated with frontotemporal dementia).

CNVs are now thought to have a greater impact on genomic diversity than do single-nucleotide changes (single-nucleotide polymorphisms, SNPs, are the most common type of genetic variation, involving a change in a single nucleotide: A, G, T, C).

http://www.eurekalert.org/pub_releases/2013-06/mgh-rgm061713.php

[3577] Hooli, B. V., Kovacs-Vajna Z. M., Mullin K., Blumenthal M. A., Mattheisen M., Zhang C., et al.
(2014).  Rare autosomal copy number variations in early-onset familial Alzheimer’s disease.
Molecular Psychiatry. 19(6), 676 - 681.