This article by Mattsson et al. is authored by an outstanding group, which investigated the effects of BACE1 inhibitors on Aβ peptide forms in media secreted from cultured neurons and in CSF after in-vivo treatment of dogs. Interestingly, the data suggest that the BACE1 inhibitors result in an altered Aβ peptide pattern, with an increase in the ratio of Aβ5-40:Aβ1-34. However, several aspects of the study should be carefully considered. Firstly, the wide range of dog ages, and the few number of dogs per group, make conclusions from the data difficult, since it is known that Aβ levels in CSF differ depending on the age of the dog (Head et al., 2010). Secondly, because a cocktail of protease inhibitors was not included in sample preparations, it is not known if the profiles of Aβ peptides observed are from the endogenous condition or if they became degraded during the in-vitro methods. Thirdly, use of standards for quantitative mass spectrometry is typical in the field, but standards were not evident in this study. Fourthly, the cell culture data reflect only Aβ produced in the...  Read more

This article by Mattsson et al. is authored by an outstanding group, which investigated the effects of BACE1 inhibitors on Aβ peptide forms in media secreted from cultured neurons and in CSF after in-vivo treatment of dogs. Interestingly, the data suggest that the BACE1 inhibitors result in an altered Aβ peptide pattern, with an increase in the ratio of Aβ5-40:Aβ1-34. However, several aspects of the study should be carefully considered. Firstly, the wide range of dog ages, and the few number of dogs per group, make conclusions from the data difficult, since it is known that Aβ levels in CSF differ depending on the age of the dog (Head et al., 2010). Secondly, because a cocktail of protease inhibitors was not included in sample preparations, it is not known if the profiles of Aβ peptides observed are from the endogenous condition or if they became degraded during the in-vitro methods. Thirdly, use of standards for quantitative mass spectrometry is typical in the field, but standards were not evident in this study. Fourthly, the cell culture data reflect only Aβ produced in the constitutive, and not regulated, secretory pathway; since a major portion of Aβ is released from the regulated secretory pathway, which utilizes cathepsin B for Aβ production (Klein et al., 2009), nothing can be inferred regarding the role of cathepsin B in producing Aβ from the study’s finding that an inhibitor of cathepsin B had no effect on constitutive Aβ secretion. Finally, the authors should indicate whether they, or other groups, have data indicating that BACE1 inhibitors improve memory deficits, the critical goal of Alzheimer’s therapeutics. It will be of interest for the authors to continue these studies to examine these important features of Aβ research.

References:
Head E, Pop V, Sarsoza F, Kayed R, Beckett TL, Studzinski CM, Tomic JL, Glabe CG, Murphy MP. Amyloid-beta peptide and oligomers in the brain and cerebrospinal fluid of aged canines. J Alzheimers Dis. 2010;20(2):637-46. Abstract

Klein DM, Felsenstein KM, Brenneman DE. Cathepsins B and L differentially regulate amyloid precursor protein processing. J Pharmacol Exp Ther. 2009 Mar;328(3):813-21. Abstract

View all comments by Vivian Hook

The study by Mattsson et al. provides clear and important evidence that specific generation of Aβ5-x is a general phenomenon under the condition of BACE1 inhibition. The authors emphasize that the Aβ pattern may be useful in monitoring the in-vivo effects of BACE1 inhibitors. However, it remains an open question by what mechanism Aβ5-x is produced.

In our previous studies (Takeda et al., 2004; Murayama et al., 2007), we demonstrated that neuroblastoma SH-SY5Y cells expressing the caspase-cleaved form of amyloid precursor protein (APP) lacking the C-terminal 31 amino acids preferentially produce Aβ5-40/42. We showed that treatment of the cells with TAPI-I, which can inhibit α-secretase, decreases Aβ5-40 and increases Aβ1-40, suggesting that α-secretase-like proteases are involved in the generation of Aβ5-40/42. We additionally observed that treatment of SH-SY5Y cells expressing wild-type APP with a BACE1 inhibitor, OM99-2, decreased Aβ1-40 with an increase of Aβ5-40, consistent with the results by Mattsson et al. Therefore, inhibition of BACE1 may lead to the distinct...  Read more

The study by Mattsson et al. provides clear and important evidence that specific generation of Aβ5-x is a general phenomenon under the condition of BACE1 inhibition. The authors emphasize that the Aβ pattern may be useful in monitoring the in-vivo effects of BACE1 inhibitors. However, it remains an open question by what mechanism Aβ5-x is produced.

In our previous studies (Takeda et al., 2004; Murayama et al., 2007), we demonstrated that neuroblastoma SH-SY5Y cells expressing the caspase-cleaved form of amyloid precursor protein (APP) lacking the C-terminal 31 amino acids preferentially produce Aβ5-40/42. We showed that treatment of the cells with TAPI-I, which can inhibit α-secretase, decreases Aβ5-40 and increases Aβ1-40, suggesting that α-secretase-like proteases are involved in the generation of Aβ5-40/42. We additionally observed that treatment of SH-SY5Y cells expressing wild-type APP with a BACE1 inhibitor, OM99-2, decreased Aβ1-40 with an increase of Aβ5-40, consistent with the results by Mattsson et al. Therefore, inhibition of BACE1 may lead to the distinct processing of APP between Phe4 and Arg5, possibly mediated by α-secretase-like proteases.

Although it is not clear whether Aβ5-x has a pathological role, our previous data indicate that Aβ5-x is particularly deposited in intermediate vessels with amyloid angiopathy in Alzheimer’s disease (AD) brains. The findings by Mattsson et al. imply that clinical application of BACE1 inhibitors to AD patients could induce the generation of Aβ5-x in the brain, which might influence the pathological processes. Thus, the pathophysiological property of this N-terminally truncated Aβ species needs further clarification.

References:
Takeda K, Araki W, Akiyama H, Tabira T. Amino-truncated amyloid β-peptide (Aβ5-40/42) produced from caspase-cleaved amyloid precursor protein is deposited in Alzheimer’s disease brain. FASEB J. 2004; 18:1755-1757. Abstract

Murayama KS, Kametani F, Tabira T, Araki W. A novel monoclonal antibody specific for the amino-truncated β-amyloid Aβ5-40/42 produced from caspase-cleaved amyloid precursor protein. J Neurosci Methods. 2007; 161:244-249. Abstract

View all comments by Wataru Araki