Chow VW, Savonenko AV, Melnikova T, Kim H, Price DL, Li T, Wong PC.
Modeling an anti-amyloid combination therapy for Alzheimer's disease.
Sci Transl Med. 2010 Jan 6;2(13):13ra1.
PubMed.
The partial inhibition of both secretases is quite interesting, and the results could easily be viewed as implicating βCTF as well as Aβ in pathology. In addition to the mechanism Chow et al. propose of additive/synergistic effects on Aβ lowering, our data would suggest that an additional explanation for the combined inhibitor effects on memory deficits are a reversal of separate adverse effects of βCTF and Aβ on cognitive performance. A third copy of APP is known to be responsible for certain of the memory and learning deficits in the Ts65Dn mouse model of Down syndrome, which is associated with increased β-cleavage of APP but no measurable Aβ elevation, at least at the whole brain level (Choi et al. 2009; Salehi et al. 2006). In light of our recent evidence linking increased βCTF to AD-related endosome defects in Down syndrome and to FAD due to APP duplication, it is reasonable to suspect that βCTF may play a role in the rescue of cognitive deficits by BACE inhibition. This would be expected to add to effects of lowering Aβ levels in the APPswe/PS1DE9 model used in this study, which exhibits marked amyloid deposition/Aβ elevation in contrast to the Ts65Dn mouse.
Based on this framework, the caveats that our work suggested regarding the possible buildup of potentially toxic βCTF after using γ inhibitor alone would be offset by simultaneously blocking CTF buildup with a BACE inhibitor.
References:
Choi JH, Berger JD, Mazzella MJ, Morales-Corraliza J, Cataldo AM, Nixon RA, Ginsberg SD, Levy E, Mathews PM.
Age-dependent dysregulation of brain amyloid precursor protein in the Ts65Dn Down syndrome mouse model.
J Neurochem. 2009 Sep;110(6):1818-27. Epub 2009 Jul 10
PubMed.
Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS, Takimoto-Kimura R, Kleschevnikov AM, Sambamurti K, Chung PP, Xia W, Villar A, Campbell WA, Kulnane LS, Nixon RA, Lamb BT, Epstein CJ, Stokin GB, Goldstein LS, Mobley WC.
Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration.
Neuron. 2006 Jul 6;51(1):29-42.
PubMed.
The new study by Chow and colleagues describes evidence that the combination of partial reductions in β-secretase and γ-secretase are effective in lowering Aβ production and deposition and preventing cognitive deficits in mice. This happens without the deleterious effects of complete knockout of either protease alone, something that many of us in the field have suspected for some time, but which had not yet been demonstrated.
The strategy for dual lowering of the two secretases was strictly genetic, not pharmacological: mice that are heterozygous knockouts of BACE1 and Aph1a were crossed into transgenic mice overexpressing AD mutant APP and Presenilin.
Nevertheless, the results provide an important proof of principle. From a practical perspective though, it will be difficult to test this combination approach in humans, as each secretase inhibitor must first be tested individually and shown to be efficacious before combination regimens can be tried.
Comments
New York University School of Medicine/Nathan Kline Institute
The partial inhibition of both secretases is quite interesting, and the results could easily be viewed as implicating βCTF as well as Aβ in pathology. In addition to the mechanism Chow et al. propose of additive/synergistic effects on Aβ lowering, our data would suggest that an additional explanation for the combined inhibitor effects on memory deficits are a reversal of separate adverse effects of βCTF and Aβ on cognitive performance. A third copy of APP is known to be responsible for certain of the memory and learning deficits in the Ts65Dn mouse model of Down syndrome, which is associated with increased β-cleavage of APP but no measurable Aβ elevation, at least at the whole brain level (Choi et al. 2009; Salehi et al. 2006). In light of our recent evidence linking increased βCTF to AD-related endosome defects in Down syndrome and to FAD due to APP duplication, it is reasonable to suspect that βCTF may play a role in the rescue of cognitive deficits by BACE inhibition. This would be expected to add to effects of lowering Aβ levels in the APPswe/PS1DE9 model used in this study, which exhibits marked amyloid deposition/Aβ elevation in contrast to the Ts65Dn mouse.
Based on this framework, the caveats that our work suggested regarding the possible buildup of potentially toxic βCTF after using γ inhibitor alone would be offset by simultaneously blocking CTF buildup with a BACE inhibitor.
References:
Choi JH, Berger JD, Mazzella MJ, Morales-Corraliza J, Cataldo AM, Nixon RA, Ginsberg SD, Levy E, Mathews PM. Age-dependent dysregulation of brain amyloid precursor protein in the Ts65Dn Down syndrome mouse model. J Neurochem. 2009 Sep;110(6):1818-27. Epub 2009 Jul 10 PubMed.
Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS, Takimoto-Kimura R, Kleschevnikov AM, Sambamurti K, Chung PP, Xia W, Villar A, Campbell WA, Kulnane LS, Nixon RA, Lamb BT, Epstein CJ, Stokin GB, Goldstein LS, Mobley WC. Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron. 2006 Jul 6;51(1):29-42. PubMed.
View all comments by Ralph NixonUniversity of Kansas
The new study by Chow and colleagues describes evidence that the combination of partial reductions in β-secretase and γ-secretase are effective in lowering Aβ production and deposition and preventing cognitive deficits in mice. This happens without the deleterious effects of complete knockout of either protease alone, something that many of us in the field have suspected for some time, but which had not yet been demonstrated.
The strategy for dual lowering of the two secretases was strictly genetic, not pharmacological: mice that are heterozygous knockouts of BACE1 and Aph1a were crossed into transgenic mice overexpressing AD mutant APP and Presenilin.
Nevertheless, the results provide an important proof of principle. From a practical perspective though, it will be difficult to test this combination approach in humans, as each secretase inhibitor must first be tested individually and shown to be efficacious before combination regimens can be tried.
View all comments by Michael WolfeMake a Comment
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