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...  Read more

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.

View all comments by Bart De Strooper

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.

View all comments by Diego Forero

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;...  Read more

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, P. A., Piper, S., Crook, R., Baker, M., Findlay, K., Singleton, A., Hogg, M., Younkin, L., Younkin, S. G., et al. (2002). A presenilin 1 mutation associated with familial frontotemporal dementia inhibits γ-secretase cleavage of APP and notch. Neurobiol Dis 9, 269-273. Abstract

Dermaut, B., Kumar-Singh, S., Engelborghs, S., Theuns, J., Rademakers, R., Saerens, J., Pickut, B. A., Peeters, K., van den Broeck, M., Vennekens, K., et al. (2004). A novel presenilin 1 mutation associated with Pick's disease but not β-amyloid plaques. Ann Neurol 55, 617-626. Abstract

Feng, R., Wang, H., Wang, J., Shrom, D., Zeng, X., and Tsien, J. Z. (2004). 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. Abstract

Saura, C. A., Choi, S. Y., Beglopoulos, V., Malkani, S., Zhang, D., Shankaranarayana Rao, B. S., Chattarji, S., Kelleher, R. J., 3rd, Kandel, E. R., Duff, K., et al. (2004). Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 42, 23-36. Abstract

Tang-Wai, D., Lewis, P., Boeve, B., Hutton, M., Golde, T., Baker, M., Hardy, J., Michels, V., Ivnik, R., Jack, C., and Petersen, R. (2002). Familial frontotemporal dementia associated with a novel presenilin-1 mutation. Dement Geriatr Cogn Disord 14, 13-21. Abstract

Theuns, J., Remacle, J., Killick, R., Corsmit, E., Vennekens, K., Huylebroeck, D., Cruts, M., and Van Broeckhoven, C. (2003). Alzheimer-associated C allele of the promoter polymorphism -22C>T causes a critical neuron-specific decrease of presenilin 1 expression. Hum Mol Genet 12, 869-877. Abstract

View all comments by Bart Dermaut