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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.View all comments by Bart De Strooper
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.View all comments by Diego Forero