Do familial Alzheimers Disease mutations cause loss or gain of function of ySecretase

Ever since the ADcausing mutations in Presenilin were identified, it has been discussed whether they contribute an abnormal gain or loss of function to Presenilin. The facts that Psen knockout in neurons results in loss of Ap peptide generation (De Strooper et al. 1998) and that all investigated clinical Psen mutations cause a "gain" in the relative amount of Ap42 peptide versus Ap40 peptide (Borchelt et al. 1996; Duff et al. 1996; Scheuner et al.,1996) have been taken as an argument for the "gain of abnormal function" hypothesis. However, in principle, such a relative change can be caused either by increased Ap42 or decreased Ap4o generation, or a combination of both changes. Rescue experiments with Psen-deficient cells using wild type Presenilin or Presenilin-containing clinical mutations provided a more definitive answer: most tested mutations caused an overall decrease in Y-Secretase cleavage efficiency of different substrates in the context of a Presenilin-negative background (Bentahir et al. 2006; see also Kumar-Singh et al. 2006a); Schroeter et al. 2003; Song et al. 1999). Rescue experiments with Presenilin-containing clinical mutations in Psen-deficient C. Elegans had also previously indicated that clinical mutations caused a loss of function in Notch signaling (Baumeister et al. 1997; Levitan et al. 1996). Rescue experiments with Psen1-deficient mice demonstrated, in contrast, that the clinical PS1-A246E mutant was able to partially rescue the Notch signaling-deficient phenotype (Davis et al. 1998; Qian et al. 1998). However, the conclusion of these experiments should likely be reconsidered since a partial rescue could still reflect a loss of function with this mutant. Indeed the loss of function effect of the PS1-A246E mutation on Y-Secretase activity is relatively mild in reconstituted Psen-deficient cells compared to other mutations (Bentahir et al. 2006). A better experiment would be to generate a knockin of this mutation into the endogenous gene and to evaluate to what extent such an affected allele is capable of restoring Notch cleavage and other Y-Secretase functions in a Psen1&2 negative background. This type of experiment has not yet been done in the absence of the Psen2 gene, but the phenotypes of three knockin mice (PS1M146V, PS1I213T, PS1P264L; Guo et al. 1999; Nakano et al. 1999; Siman et al. 2000); Wang et al. 2006) is quite normal, indicating that the loss of function caused by these mutations on Notch signaling is mild at the "physiological level." In contrast, in all cases Ap42 peptide is increased relative to Ap40. In patients and animals, the effect of a partial loss of function allele in the context of two or three other healthy alleles (two Psen2 and one Psenl, depending on the case) is quite difficult to predict. Clearance factors, compensatory mechanisms, and additional pathogenetic factors can considerably complicate the picture. It is likely that a FAD mutation in one single Psenl allele will not dramatically affect the total Ap peptide production in brain since the healthy Psen alleles will compensate for the partial loss of the diseased Presenilin function. It is also possible that in vivo APP-CTF substrate accumulates as a consequence of the partial loss of function of the FAD-PS1, which then would lead to a new steady state situation and more substrate again driving Aß peptide generation. Compared to the normal situation, this could theoretically result in quantitatively similar levels of Aß peptide but qualitatively higher amounts of the Aß42 variant. Even a small relative increase of Aß42 peptide variant could critically affect Aß amyloid deposition and generation of the putative toxic Aß oligomer form. Recently, the effect of clinical Presenilin mutations in the context of wild type alleles was investigated in mice and it was shown that, in line with these assumptions, a wild type Psenl allele acted protectively against amyloidosis (Wang et al. 2006).

Does the loss of Presenilin function contribute in other ways to AD? Indeed, in conditional targeted mice in whichboth Psen1&2 alleles were inactivated, a progressive neurodegenerative disorder was observed in the absence of Aß deposition (Saura et al. 2004). The hypothesis that Presenilin loss of function contributes to AD is, however, difficult to explain in the context of sporadic AD and especially familial AD with APP mutations. Hypotheses that do not take into account Aß peptide toxicity do not explain how, for instance, the Swedish APP mutation (Mullan et al. 1992) causes AD. This mutation increases absolute amounts of Aß peptide but does not affect, as far as we know, Presenilin function.

The amyloid hypothesis has a big advantage in that it accommodates APP mutations, APP gene duplications, Presenilin mutations and the presence ofamyloid plaques in genetic as well as in sporadic AD. It is clear that tangles have only recently been incorporated in the hypothesis, downstream of Aß peptide toxicity. Putting tangles downstream of Aß is consistent with the genetic mutations in Tau (FTD-17) that cause tangles but not amyloid plaques. Of course, the amyloid hypothesis will evolve over the years to further incorporate new experimental findings. The amyloid hypothesis accounts for many more experimental data than any other theory in the Alzheimer literature and therefore provides a very strong theoretical framework for Alzheimer's research. The only way forward now is to perform the critical experiments in the clinic by treating patients with anti-Aß peptide therapies, and y-Secretase modifiers or inhibitors could be one of those therapies.

Martin Citron

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