. BACE1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system. PLoS One. 2012;7(2):e31084. PubMed.

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  1. 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:

    . Amino-truncated amyloid beta-peptide (Abeta5-40/42) produced from caspase-cleaved amyloid precursor protein is deposited in Alzheimer's disease brain. FASEB J. 2004 Nov;18(14):1755-7. PubMed.

    . A novel monoclonal antibody specific for the amino-truncated beta-amyloid Abeta5-40/42 produced from caspase-cleaved amyloid precursor protein. J Neurosci Methods. 2007 Apr 15;161(2):244-9. PubMed.

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