The Senility-Presenilin Connection Turned Upside Down
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Surprising as it may seem, presenilins—the enzymes at the heart of the proteolytic γ-secretase complex that unleashes Aβ peptides—are essential to prevent age-related cognitive deficits and neurodegeneration. That's the conclusion from research carried out in Jie Shen's lab at Brigham and Women's Hospital, Boston. Shen presented the data at the Society for Neuroscience meeting in New Orleans last year (see ARF related news story), and published yesterday in the online version of Neuron, due out in print next week.
Because presenilins are essential for embryonic development, first author Carlos Saura and colleagues used a technique called a conditional knockout to eliminate expression of the two presenilin genes in the forebrain of postnatal mice. The mice then developed age-dependent neurodegeneration, scoring progressively worse in tests designed to measure their memory and learning ability. Saura and colleagues correlated these declines with dysregulation of several signal transduction pathways, including those involving NMDA receptors/CaMKII, CREB/CBP, and with increased activity of Cdk5/p25 and hyperphosphorylated tau. (Tau is the major protein in the intracellular neurofibrillary tangles that clog the neurons of Alzheimer's patients, and Cdk5 phosphorylates tau.)
Presenilin mutations are one cause of familial Alzheimer's disease. These mutations have long been said to be gain-of-function, i.e., they increase cleavage of the Aβ precursor protein and release more Aβ, which may then end up in amyloid plaques if it is not cleared quickly enough. Shen’s new data does not dispute this, but suggests that PS mutations may also cause a loss of function that contributes to the pathology of AD and complicates the picture. The data also suggests that discretion should be the better part of valor when it comes to γ-secretase inhibitors as potential AD therapeutics.—Tom Fagan
References
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Primary Papers
- Saura CA, Choi SY, Beglopoulos V, Malkani S, Zhang D, Shankaranarayana Rao BS, Chattarji S, Kelleher RJ 3rd, Kandel ER, Duff K, Kirkwood A, Shen J. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron. 2004 Apr 8;42(1):23-36. PubMed.
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UK Dementia Research Institute@UCL and VIB@KuLeuven
I am quite impressed by this paper, which dives very deep and is of high quality. The observations raise two important issues:
1. Given the apparent central role of the presenilins in memory, and given the fact that loss of presenilins causes neurodegeneration, is it possible that presenilin dysfunction at least partially contributes to the neurodegenerative process in some familial forms of Alzheimer's? In my opinion, we indeed still have to learn a lot about the fundamental processes of neurodegeneration in Alzheimer's disease, and this paper contributes significantly to that aim.
2. What are the implications of the findings for drug development programs trying to target presenilin/γ-secretase? The second issue is not the main message of this paper, but obviously it is a question that will be raised by many researchers and managers in companies. My opinion is that a genetic knockout and a pharmacological modulation of a protein are two very different situations. For example, the HMGCoA reductase knockout gives a very early lethal phenotype—still statins are one of the most widely used drugs in the world. Thus, I would say that it is absolutely necessary to continue with the γ-secretase inhibitor programs, especially with programs that try to develop "modulators" of the protease (like the NSIADs.) (Editor's note: see ARF related news story.) It is important to find compounds that discriminate between APP processing and Notch processing. Once those are found, only clinical trials will allow us to make real decisions about the viability of these drugs. We have few options in Alzheimer's disease treatment; thus, it would be unwise to drop too quickly any potential approach for treatment.
National University of Colombia
This is a key paper for the actual and future understanding of the pathogenesis of Alzheimer's disease. With very interesting, complete and provocative findings, the paper shows that in adult brain the total lack of presenilin function leads to early functional alterations (LTP and memory failure) that some months later are followed by morphological and structural changes (loss of neurons). The paper also highlights the importance of the study of AD models from an experimental interdisciplinary approach in a longitudinal way.
We are very intrigued by the two recent papers (Feng et al., 2004; Saura et al., 2004) showing neurodegeneration and tau hyperphosphorylation in PS null mouse brains. Although at first sight the non-amyloid neuropathology doesn’t appear to be directly relevant to AD, these studies nevertheless clearly challenge the currently widely accepted view that AD-related PS mutations are gain of function mutations (as measured by amyloid-β deposition/secretion).
In this context, it is of interest that we have recently published a paper (Dermaut et al., 2004) reporting a novel PS1 mutation in a patient with a pure tauopathy (Pick’s disease, a subtype of FTD) but without any detectable amyloid deposits. Moreover, preliminary evidence on the molecular nature of this mutation suggests that it might act as a partial loss-of-function allele due to aberrant exon splicing, which would be in agreement with the loss of function/dominant negative mechanism that has been proposed for another PS1 mutation (insArg352) associated with FTD, though not pathologically confirmed (Amtul et al., 2002; Tang-Wai et al., 2002). In addition, we have shown that lowered neuronal expression of PS is genetic risk factor for early onset AD (Theuns et al., 2003), Although still highly speculative, these studies together appear to raise the exciting possibility that, in humans, partial loss of PS function could result in primarily tau-mediated neurodegenerative pathways.
References:
Amtul Z, Lewis PA, Piper S, Crook R, Baker M, Findlay K, Singleton A, Hogg M, Younkin L, Younkin SG, Hardy J, Hutton M, Boeve BF, Tang-Wai D, Golde TE. A presenilin 1 mutation associated with familial frontotemporal dementia inhibits gamma-secretase cleavage of APP and notch. Neurobiol Dis. 2002 Mar;9(2):269-73. PubMed.
Dermaut B, Kumar-Singh S, Engelborghs S, Theuns J, Rademakers R, Saerens J, Pickut BA, Peeters K, van den Broeck M, Vennekens K, Claes S, Cruts M, Cras P, Martin JJ, Van Broeckhoven C, De Deyn PP. A novel presenilin 1 mutation associated with Pick's disease but not beta-amyloid plaques. Ann Neurol. 2004 May;55(5):617-26. PubMed.
Feng R, Wang H, Wang J, Shrom D, Zeng X, Tsien JZ. Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer's presenilin-1 and presenilin-2. Proc Natl Acad Sci U S A. 2004 May 25;101(21):8162-7. PubMed.
Saura CA, Choi SY, Beglopoulos V, Malkani S, Zhang D, Shankaranarayana Rao BS, Chattarji S, Kelleher RJ 3rd, Kandel ER, Duff K, Kirkwood A, Shen J. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron. 2004 Apr 8;42(1):23-36. PubMed.
Tang-Wai D, Lewis P, Boeve B, Hutton M, Golde T, Baker M, Hardy J, Michels V, Ivnik R, Jack C, Petersen R. Familial frontotemporal dementia associated with a novel presenilin-1 mutation. Dement Geriatr Cogn Disord. 2002;14(1):13-21. PubMed.
Theuns J, Remacle J, Killick R, Corsmit E, Vennekens K, Huylebroeck D, Cruts M, Van Broeckhoven C. Alzheimer-associated C allele of the promoter polymorphism -22C>T causes a critical neuron-specific decrease of presenilin 1 expression. Hum Mol Genet. 2003 Apr 15;12(8):869-77. PubMed.
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