Presenilin-1
(PS1) is a catalytic subunit of the gamma-secretase complex,
an endoprotease complex that catalyzes the intramembrane
cleavage of integral membrane proteins such as Notch receptors
and APP (beta-amyloid precursor protein). The other members
of the gamma-secretase complex are required to have a protease
activity. PS1 may play a role in intracellular signaling
and gene expression or in linking chromatin to the nuclear
membrane. It regulates epithelial-cadherin function. Three
causative genes have been identified that when mutated
lead to presenile Alzheimer's disease: APP (amyloid precursor
protein gene), PSEN1 and PSEN2. These three genes account
for half of the families with autosomal dominant presenile
AD, which represent approximately 10% of the whole AD population.
In addition, apolipoprotein E has been identified as a
risk-modifying locus. Defects in PSEN1 are a cause of familial
early-onset Alzheimer disease type 3 (AD3). AD3 is the
most severe form of the disease, with complete penetrance
and an onset occurring as early as 30 years of age. The
second form is late-onset AD (LOAD), with mean age of onset
greater than 58 years. AD is an autosomal dominant neurodegenerative
disorder characterized by progressive dementia, parkinsonism,
and deposition of fibrillar amyloid proteins as intraneuronal
neurofibrillary tangles, extracellular amyloid plaques
and vascular amyloid deposits. The major protein found
within these deposits is a small, insoluble and highly
aggregating polypeptide, beta-amyloid protein (beta-APP42).
Defects in PSEN1 result in an overproduction of beta-APP42.
Variant Pro-166, a very aggressive mutation that causes
onset of AD3 in adolescence, not only induces an exceptionally
high increase of beta-APP42 production, but also impairs
Notch intracellular domain production and Notch signaling,
as well as beta-APP intracellular domain generation.
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