It is very satisfying to see a totally independent confirmation of our work, especially when important conclusions are directly attached to it.

After we identified PS1 as essential for γ-secretase activity (De Strooper et al., 1998) we all hoped it would be a—if not the—major therapeutic target in AD.

But in 2002 we had to report that the neuron-specific knockout of PS1 did not rescue the cognitive defects of APP mice, despite the nearly complete elimination of plaque and vascular amyloid pathology in old APPxPS1(n-/-) mice (Dewachter et al., 2002). The outcome was a complete and major surprise for us, difficult to explain and impossible to get past the referees of more than one major journal…and a major blow to the therapeutic potential of γ-secretase inhibitors in AD.

We believe that, despite the criticism on the non-physiological "total KO problem," the outcome of the paper of Saura et al., and of our 2002 paper, is as relevant now as it was then—and for more than one reason.

Inhibition of PS1—or "modulation" if so preferred—will result in accumulation of...  Read more

It is very satisfying to see a totally independent confirmation of our work, especially when important conclusions are directly attached to it.

After we identified PS1 as essential for γ-secretase activity (De Strooper et al., 1998) we all hoped it would be a—if not the—major therapeutic target in AD.

But in 2002 we had to report that the neuron-specific knockout of PS1 did not rescue the cognitive defects of APP mice, despite the nearly complete elimination of plaque and vascular amyloid pathology in old APPxPS1(n-/-) mice (Dewachter et al., 2002). The outcome was a complete and major surprise for us, difficult to explain and impossible to get past the referees of more than one major journal…and a major blow to the therapeutic potential of γ-secretase inhibitors in AD.

We believe that, despite the criticism on the non-physiological "total KO problem," the outcome of the paper of Saura et al., and of our 2002 paper, is as relevant now as it was then—and for more than one reason.

Inhibition of PS1—or "modulation" if so preferred—will result in accumulation of CTF of APP and of a bunch of other transmembrane proteins. I asked in one of my previous comments on this site: Who is keeping tally on the substrates of γ-secretase? At least for the β-CTF (C99) of APP, we know they are potentially as neurotoxic as the amyloid peptides, and probably even more, since they remain attached to, and concentrated in the neurons in which they are produced. We do not know much about the (non-) physiological repercussions of remnants of other substrates of γ-secretase, but their accumulation can be safely predicted to be "not good for your brain."

The prevention of formation of AICD by inhibition of γ-secretase can or should be added to the drawbacks, now even more than in 2002, given the most recent evidence that AICD actually regulates expression of neprilysin (Pardossi-Piquard et al., 2005), that, as we all know, is a major Aβ killer!

Does that imply that the γ-secretase complex is off-bounds as a therapeutic target for AD as we advocated before (Dewachter and Van Leuven, 2002) based on our 2002 data? I believe so, but not being clairvoyant, I cannot but leave the question open. Nevertheless, the structural and functional complexity of γ-secretase, the inherent and not understood control of its activity and specificity, combined with the disparity of its substrates in neurons and in many (most?) other cell types in our body, is so overwhelming that finding weak spots or leap holes in its armor is a daunting task.

References:
Dewachter I, Reverse D, Caluwaerts N, Ris L, Kuiperi C, Van den Haute C, Spittaels K, Umans L, Serneels L, Thiry E, Moechars D, Mercken M, Godaux E, Van Leuven F. Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice. J Neurosci. 2002 May 1;22(9):3445-53. Abstract De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998 Jan 22;391(6665):387-90. Abstract Dewachter I, Van Leuven F. Secretases as targets for the treatment of Alzheimer's disease: the prospects. Lancet Neurol. 2002 Nov;1(7):409-16. Review. Abstract Pardossi-Piquard R, Petit A, Kawarai T, Sunyach C, Alves da Costa C, Vincent B, Ring S, D'Adamio L, Shen J, Muller U, St George Hyslop P, Checler F. Presenilin-dependent transcriptional control of the Aβ-degrading enzyme neprilysin by intracellular domains of βAPP and APLP. Neuron. 2005 May 19;46(4):541-54. Abstract

View all comments by Fred Van Leuven

This paper is one of the most interesting contributions of the year, and may well be one of the most informative animal models of AD yet published. To fully appreciate it, readers should first read two prior papers from this same group in which they systematically analyze the consequences of conditionally knocking out PS1 activity under different conditions. If PS1 is knocked out in postnatal neurons, PS2 can compensate, unless the APP load is excessive, as is the case when the PS1 KO is generated in animals bearing mutant forms of APP. The big surprise is that animals with such combinations do not generate large amounts of amyloid material, yet they eventually become as mentally disabled as those who do have large Aβ deposits. Predictably, these animals also generate large amounts of the APP C-terminal peptide, C-99, the consequence of an almost total lack of γ-secretase activity. Why neuronal dysfunction follows is the big question, since the secreted form of Aβ should not be a factor. The authors believe that the accumulation of C-99 may be responsible for the memory...  Read more

This paper is one of the most interesting contributions of the year, and may well be one of the most informative animal models of AD yet published. To fully appreciate it, readers should first read two prior papers from this same group in which they systematically analyze the consequences of conditionally knocking out PS1 activity under different conditions. If PS1 is knocked out in postnatal neurons, PS2 can compensate, unless the APP load is excessive, as is the case when the PS1 KO is generated in animals bearing mutant forms of APP. The big surprise is that animals with such combinations do not generate large amounts of amyloid material, yet they eventually become as mentally disabled as those who do have large Aβ deposits. Predictably, these animals also generate large amounts of the APP C-terminal peptide, C-99, the consequence of an almost total lack of γ-secretase activity. Why neuronal dysfunction follows is the big question, since the secreted form of Aβ should not be a factor. The authors believe that the accumulation of C-99 may be responsible for the memory deterioration, and they offer microscopic evidence that these peptides concentrate in synaptic terminals, but several questions remain to be answered. In which subcellular compartment do they accumulate? Do they exist as dimers that are still embedded within lipid raft domains of membranes? If so, why don’t the variant secretases (δ, ε) and the membrane-associated ADAM proteases digest them into smaller hydrophobic peptides? These could conceivably remain within the membrane interior for long periods and behave as toxic elements. In addition to these APP related questions, having compromised amounts of PS1 raises another set of problems for such animals, given the wide range of physiological intramembranous cleavages (RIPs) that are known to require PS1 collaboration.

I am impressed that these animals develop neurological problems, reminiscent of clinical AD, without the accumulation of vast amounts of extracellular deposits of Aβ peptides. One has to wonder whether the earliest forms of the human disease share these characteristics, with the intracellular accumulation of as yet unidentified toxic APP products preceding the development of amyloidosis.

View all comments by Vincent Marchesi

Interesting piece of work. The more sophisticated these models are, the more you can conclude one way or another. Is this model suggesting to kill presenilin to cure AD? Of course not, but data are in favor of that.

What if the explanation of the beneficial effect is linked to the prevention of the inflammatory response?

View all comments by Andre Delacourte

Another Disconnect between Amyloid and Cognition
Saura and colleagues (2005), like Van Leuven before (Dewachter et al., 2002), demonstrate a clear disconnect between amyloid-β and cognitive decline. As such, while it is clear that mutations in APP cause disease, the mechanism(s) by which mutations cause the disease is far from clear. The fact that cognitive deficits are apparent in PS1 cKO/PDAPP mice indicates that amyloid-β is unlikely to be involved, and that the worsening of cognition with age points to other mechanisms (Nunomura et al., 2004). Notably, the fact that PS1 cKO/PDAPP lacking amyloid-β fare worse than PDAPP animals with amyloid-β might even indicate that amyloid-β is beneficial in certain circumstances as we previously indicated (Nunomura et al., 2001; Rottkamp et al., 2001; Lee et al., 2004).

Hyoung-gon Lee, Xiongwei Zhu, George Perry, Mark Smith

References:
Dewachter I, Reverse D, Caluwaerts N, Ris L, Kuiperi C, Van den Haute C, Spittaels K, Umans L, Serneels L, Thiry E, Moechars D, Mercken M, Godaux E, Van Leuven F. Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice. J Neurosci. 2002 May 1;22(9):3445-53. Abstract.

Lee HG, Casadesus G, Zhu X, Takeda A, Perry G, Smith MA. Challenging the amyloid cascade hypothesis: senile plaques and amyloid-beta as protective adaptations to Alzheimer disease. Ann N Y Acad Sci. 2004 Jun;1019:1-4. Abstract.

Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001 Aug;60(8):759-67. Abstract.

Nunomura A, Chiba S, Lippa CF, Cras P, Kalaria RN, Takeda A, Honda K, Smith MA, Perry G. Neuronal RNA oxidation is a prominent feature of familial Alzheimer's disease. Neurobiol Dis. 2004 Oct;17(1):108-13. Abstract.

Rottkamp CA, Atwood CS, Joseph JA, Nunomura A, Perry G, Smith MA. The state versus amyloid-beta: the trial of the most wanted criminal in Alzheimer disease. Peptides. 2002 Jul;23(7):1333-41. Abstract.

Saura CA, Chen G, Malkani S, Choi SY, Takahashi RH, Zhang D, Gouras GK, Kirkwood A, Morris RG, Shen J. Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice. J Neurosci. 2005 Jul 20;25(29):6755-64. Abstract.

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