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Filser S, Ovsepian SV, Masana M, Blazquez-Llorca L, Brandt Elvang A, Volbracht C, Müller MB, Jung CK, Herms J. Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions. Biol Psychiatry. 2015 Apr 15;77(8):729-39. Epub 2014 Oct 29 PubMed.
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German Center for Neurodegenerative Diseases (DZNE)
This is an interesting paper, which fits well with earlier findings reported from Phil Wong’s lab in BACE1-deficient mice (Savonenko et al., 2008). After Carmen Birchmeier’s report last year (Cheret et al., 2013), this is now another story demonstrating that BACE inhibitors can have side effects in adult animals. This is a finding we need to consider for clinical trials.
On the other hand, many of the findings reported in this new paper show up with the high, but not the low, concentration of inhibitors. Thus, with careful dosing of the inhibitor in patients, there may be a chance to avoid these side effects. Additionally, the phenotypes largely do not show up in BACE1-deficient mice compared to wild-type mice, which may be due to compensatory changes in the BACE1-deficient mice, as the authors speculate. Thus, it remains possible that similar compensatory (and side effect-preventing) changes would show up if the inhibitor was given not just for two weeks, but for several weeks or months—similar to the long-term dosing in an AD patient.
For the future, it will be important to identify the substrate(s) that mediate the spine phenotype and to see whether this is mediated by neuregulin (see, e.g., Savonenko et al., 2008). Additionally, it would be helpful to confirm the phenotype in a second BACE1-deficient mouse model, as not all phenotypes appear to be shared by all BACE1-deficient mouse lines.
References:
Savonenko AV, Melnikova T, Laird FM, Stewart KA, Price DL, Wong PC. Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5585-90. PubMed.
Cheret C, Willem M, Fricker FR, Wende H, Wulf-Goldenberg A, Tahirovic S, Nave KA, Saftig P, Haass C, Garratt AN, Bennett DL, Birchmeier C. Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles. EMBO J. 2013 Jun 21; PubMed.
UCB Pharma Belgium
Over the last years a number of studies have addressed potential on-target liabilities of therapeutic BACE1 inhibition. Many of these studies were based on knockout data alone, or addressed developmental myelination. In contrast, the new study by Herms and colleagues investigates the effects of two drug-like BACE1 inhibitors in adult mice. It reports negative effects on synaptic plasticity. While these relatively subtle effects would not have been picked up in standard toxicology studies, the data suggesting that the BACE1 inhibitor SCH1682496 alters dendritic spine dynamics in vivo appears robust and more concerning than mouse behavior data. Interestingly, the effect is seen only at the higher dose, while Aβ is already substantially reduced at the lower dose.
Clearly, these results deserve further follow up to see whether they are universally observed with all BACE1 inhibitors and whether they translate to other species and to humans. If that is the case, then dosing to a target level of plasma Aβ reduction would be preferable to “flooring” the signal.
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