Voytyuk I, Mueller SA, Herber J, Snellinx A, Moechars D, van Loo G, Lichtenthaler SF, De Strooper B. BACE2 distribution in major brain cell types and identification of novel substrates. Life Science Alliance Feb 2018

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  1. I read this paper with interest. There are many substrates besides VCAM1 that might be altered as a result of BACE-2 inhibition, with potentially unknown effects on the brain. The magnitude of alteration was clearly higher in the presence of TNF-α, which may be relevant to AD as this may be produced by microglia and astrocytes.

    I am not clear that BACE2 cleavage would alter overall bulk levels of VCAM1 in CSF, because the BACE2 mRNA was predominantly expressed in neurons, oligodendrocytes, and cells lining the lateral ventricle, and VCAM1 release may be the predominant result of other pathways taking place in vascular cells. 

    We had previously looked at CSF VCAM1 with the idea that it might be a vascular-related biomarker, because it is expressed at high levels in CNS endothelial cells. I am unaware of VCAM1 or other proteins being reported from CSF in humans receiving BACE inhibitors. The neuropsychiatric symptoms reported in the verubacestat clinical trial have received some discussion at CTAD 2017 (Dec 2017 conference news), and I wonder if a subtle dysregulation of secreted molecules cleaved by BACE2 might have contributed or serve as markers of those symptoms?

    View all comments by Douglas Galasko

  2. This is a good study that raises the potential side effects of current BACE inhibitors (which do not discriminate BACE1 versus BACE2) due to impact on substrates of BACE2, particularly under pathological conditions.

    As it is not clear whether this information can be translated directly to humans, or whether such off-target effects would be substantial in patients with AD, the main lesson here is that it will be important to monitor for potential side effects related to pathways impacted by BACE2 inhibition during BACE1 inhibitor clinical trials.

    It would be useful to examine the brains and periphery of patients treated with the Merck BACE inhibitor verubecestat for evidence of whether these substrates of BACE2 are altered, and secondly whether abnormalities related to these targets can be shown.​

    View all comments by Philip Wong

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  1. Remember: BACE2 Is in the Brain, Too