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Home > A. Molecular pathology > PSENs


Wednesday 29 October 2003

Definition: Presenilin proteins (PSENs) are transmembrane proteins that function as a part of the γ-secretase protease complex.

Vertebrates have two presenilin genes, called presenilin1 (PSEN1) and presenilin 2 (PSEN2), whereas invertebrates such as Drosophila have only a single presenilin.

Mutations in the presenilin genes are known to cause early onset Alzheimer disease (AD). By far, most early AD mutations are located in PSEN1.


- presenilin-1 (PSEN1)
- presenilin-2 (PSEN2)


The phenotypic spectrum associated with PSEN mutations appears to be broad, ranging from phenotypes strongly resembling the APP mutations at the α-secretase-cleavage site to FTD without Aβ pathology.

- early onset Alzheimer disease or presenile Alzheimer disease

Alzheimer disease-causing PSEN mutations have intrinsic loss-of-function properties and PSEN loss-of-function has a role in FTD and amyloid-independent neurodegeneration.

MAPT (tau protein) has a primary genetic role of in the frontotemporal dementia complex (FTD complex) of diseases.

Since the identification of mutations in PSENs, the most common cause of inherited presenile Alzheimer disease (AD), 154 different PS mutations (144 in PSEN1 and ten in PSEN2), mostly of the missense type, have been identified (see [AD Mutation Database-À]).

Similar to mutations at the β- or γ-secretase-cleavage sites, PSENs mutations generally result in typical AD phenotypes with amyloid plaques and tau neurofibrillary tangles (NFTs).

In addition, AD-causing PSENs mutations increase the in vitro ratio of Aβ42 to Aβ40?, and it is now well established that PSENs are a core component if not the catalytic subunit of the multimeric γ-secretase.

In general, patients with PSEN1 mutations have a more aggressive disease course and earlier age of onset compared with those carrying PSEN2 mutations.

PSENs mutations appear capable of inducing a relatively wide spectrum of clinical and neuropathological phenotypes. However, some PSENs mutations, particularly in cases in which the mutation lies beyond codon 200, are associated with a prominent cerebral amyloid angiopathy (CAA), sometimes, even reminiscent of the Flemish APP A692G α-secretase mutation (e.g. the PSEN1 L282V mutation).

In contrast to mutations at the APP α-secretase-cleavage site and with one reported exception, PSENs-related cerebral amyloid angiopathy (CAA) is generally not sufficiently severe to cause haemorrhagic strokes.

Another type of PSEN mutations leads to ‘variant’ Alzheimer disease (AD), presenting with spastic paraparesis and diffuse ‘cotton wool’ plaques, similar to those observed in carriers of the Austrian APP mutation. It was suggested that cases with ‘variant’ AD represent an aggressive subtype of AD because PSEN mutations causing this condition lead to exceptionally high in vitro amyloid concentrations.

Nevertheless, although these PSENs mutations have interesting and unusual features, they are consistent with aberrant APP processing being the primary underlying mechanism in these disorders.

Again, it is important to emphasize that all these PSEN mutations also lead to prominent tau (MAPT) pathology, albeit to a different extent.

Unfortunately, no studies are available that, similar to cerebral amyloid angiopathy (CAA), have systematically addressed whether the severity of tau pathology (MAPT) is also determined by PSEN mutation position.

Frontotemporal dementia (FTD)

The phenotypic spectrum of PSENs mutations has been extended to frontotemporal dementia (FTD). For example, PSEN1 L113P, G183V and insArg352 were identified in families with clinical FTD.

Interestingly, neuropathological examination in a patient with PSEN1 G183V revealed tauopathy in the form of Pick bodies and complete absence of amyloid plaque pathology.

Consistent with the idea that PSEN mutations can produce Pick bodies, co-existent AD and Pick body pathology was observed in patients with PSEN1 M146L and A260V mutations.

Loss of PSENs in amyloid-independent neurodegeneration

Conditional knockout mice lacking both PSENs in the post-natal forebrain showed progressive synaptic impairments and, importantly, severe age-dependent neurodegeneration characterized by cytoplasmic accumulations of hyperphosphorylated tau 71 and 72 but no Aβ deposits.

Complete loss of PSENs can lead to an amyloid-independent form of tau-positive neurodegeneration, recent findings of PSEN mutations in FTD become highly intriguing.

It was suggested that the PSEN1 G183V mutation, which is associated with FTD and with tauopathy in the form of Pick’s disease but not with Aβ plaques, might also have loss-of-function properties because it affects the splice signal at the junction of the sixth exon and intron. Interestingly, follow-up studies indeed revealed that this mutation, in addition to producing full-length PSEN1 G183V protein, also generates alternative transcripts that either lack exon six or exons six and seven leading to truncated proteins.

In addition, cellular γ-secretase assays show that the truncated proteins behave as complete null alleles also suggesting a loss-of-function mechanism.

Strikingly, a loss-of-function mechanism has also been proposed for the PS1 insArg352 mutation that strongly inhibits γ-secretase cleavage of both Notch and APP and is associated with FTD without amyloid pathology.

Although additional confirmation is needed to establish a role of PS in amyloid-independent FTD, these studies suggest that throughout the PS spectrum of disorders, ranging from AD with a strong amyloid component to possibly tau-positive, partial PS loss-of-function might be the common theme, an idea that is also supported by studies suggesting that AD-risk-increasing alleles in the regulatory region of PS1 significantly decrease PS expression levels.

In addition, several recent cell biological studies have suggested that PS mutations through reduced PI3K-Akt signaling promote glycogen synthase kinase 3β (GSK3β) activity and hence tau hyperphosphorylation, further suggesting a direct mechanistic link between PS loss-of-function and tau pathology.

Another line of recent evidence has linked dysfunction of the endosomal-lysosomal degradative system to loss of PS function. This is interesting, because neurodegeneration is a frequent observation in lysosomal disorders and abnormalities in the endosomal-lysosomal system have long been thought to be an early and prominent feature in AD.

In addition, tauopathy in the form of tau tangles is a highly consistent feature in the lysosomal disorder Niemann-Pick Type C that, in its adult onset form, can present with FTD-like dementia.

Strikingly, the recent finding that mutations in the charged multivesicular body protein 2B (CHMBP2B) on chromosome 3 cause FTD further implicates dysfunctional late-endosomal or lysosomal activity in neuronal degeneration.


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