Familial AD comprises <5% of cases and is associated with a distinct autosomal genetic mutation associated with the amyloid precursor protein (APP), presenilin-1 (PSEN-1), and presenilin-2
(PSEN-2) [5, 12-18].
Presenilins are transmembrane proteases that in humans are represented by two homologs, presenilin-1 (PS-1) and presenilin-2
(PS-2), encoded by two gens, PSEN1 and PSEN2, respectively .
Three dominant inherited mutations in the genes amyloid precursor protein (APP), presenilin-1 (PS1), and presenilin-2
(PS2), which increase the production of amyloid-beta (A[beta]) peptides, have been linked to EOAD [9, 10].
This complex is a multisubunit protease comprised of four components: presenilin-1 and presenilin-2
(PS1 and PS2, resp.), nicastrin, anterior pharynx defective-1 (APH-1), and presenilin enhancer 2 (PEN-2).
In FAD the cause of the disease is a genetic mutation in the genes coding for the amyloid precursor protein (APP), presenilin-1 (PS1) or presenilin-2
mutation causes early amyloid accumulation and memory impairment in a transgenic mouse model of Alzheimer's disease," Journal of Biomedicine and Biotechnology, vol.
In addition to the ApoE gene, identification of early onset AD can also be furthered by isolation of the three autosomal dominant genes--presenilin-1, presenilin-2
, and amyloid precursor protein gene--which account for many of the early onset cases of the disease, defined as symptomatic before age 60.
Risk factors for Alzheimer's disease Sociodemographic Increasing age, female, low educational levels Familial and genetic Family history Chromosome 1 (Presenilin-2
mutation) Chromosome 14 (Presenilin-1 mutation) Chromosome 21 (ApPP mutation) Down's syndrome (ApPP over expression) Medical history Head trauma Table 3.
These included the presenilin-2
gene, which mediates the conversion of APP into beta-amyloid.
Potter's group studied two proteins called presenilin-1 and presenilin-2
. If a person inherits two mutant copies of either presenilin-encoding gene, the abnormal proteins cause Alzheimer's disease to strike early, often before age 50 (SN: 3/2/96, p.
van den Brande et al., "Identification of caspases that cleave presenilin-1 and presenilin-2
. Five presenilin-1 (PS1) mutations do not alter the sensitivity of PS1 to caspases," FEBS Letters, vol.