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Ou-Yang MH, Kurz JE, Nomura T, Popovic J, Rajapaksha TW, Dong H, Contractor A, Chetkovich DM, Tourtellotte WG, Vassar R. Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice. Sci Transl Med. 2018 Sep 19;10(459) PubMed.
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German Center for Neurodegenerative Diseases (DZNE)
This excellent and carefully conducted study finally demonstrates that most of the phenotypes observed so far in BACE1-deficient mice are of developmental origin and may not be a cause of concern for the BACE inhibitors tested in the clinic. Yet, the authors also show that one phenotype persists in adult BACE1 KO mice, namely a structural disorganization within the mossy fibers. This phenotype adds to a, so far, short list of adult phenotypes that were detected in BACE inhibitor-treated mice, which comprise muscle spindle alterations as well as changes in LTP and dendritic spines.
Is the new adult phenotype a concern for BACE inhibitors in clinical trials? The authors carefully discuss this point, and I agree that a careful choice of the inhibitor dose may allow enough BACE1 activity to prevent such phenotypes in patients. In fact, BACE inhibitors may be more efficient in prevention than in treatment trials and a lower dose may be sufficient for prevention than for treatment.View all comments by Stefan Lichtenthaler
Johns Hopkins University
Finding a safe therapeutic window in which the dose range of BACE1 inhibitors is adjusted between tolerable mechanism-based toxic effects and Aβ reduction will be crucial to achieve a safe AD therapy. Although Bace1null mice abolish amyloid generation, they present complex cognitive and neurochemical phenotypes suggesting that BACE1 has diverse physiological functions beyond APP processing. However, little was known of whether the Bace1null phenotypes were caused by absence of BACE1 during development or whether they would also be present when BACE1 activity was inhibited in adult brain. The group of Robert Vassar shows now that the conditional knockout mice for BACE1 clearly overcome most of the Bace1null defects. This strongly suggests that BACE1 plays very important roles during brain development.
However, BACE1 conditional knockout mice still exhibit axonal disorganization in the mossy fiber pathway of the hippocampus. This phenotype mimics the CHL1null phenotype and has been previously linked to the abnormal processing of CHL1 by BACE1. L1 family cell adhesion molecules have been linked to diverse functions in the developing brain but little is known about their functions in adults. Ou-Yang’s findings once again emphasize that BACE inhibitors for Alzheimer's disease therapy should be monitored with caution and take into consideration potential mechanism-based side effects. Nonetheless, it is important to emphasize that the risk of mechanism-based toxic effects might depend on the level of BACE1 inhibition. What are the doses of inhibition that would allow BACE1 function in the mossy fiber pathway and effective reduction of amyloid levels? Finding ways to monitor the mossy fiber circuitry in ongoing clinical trials will be critical to understand the risks of BACE1 inhibition and its potential as a therapeutic target for the disease.View all comments by Soraia Barao
Biomedizinisches Centrum (BMC), Biochemie & Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)
This is a study the entire field has been waiting for, for a long time. After the initial finding that BACE1 is required for myelination via neuregulin 1 processing back in 2006 (!) (Hu et al., 2006; Willem et al., 2006), a number of other substrate-related phenotypes were observed in BACE1 knockout mice (Lichtenthaler et al., 2018). However, phenotypes like hypomyelination were most likely developmental phenotypes and may not be observed upon reduction of BACE1 in adulthood. The discrimination of developmental versus adult phenotypes is not just of academic interest, but is of greatest importance for the safety of current clinical trials using BACE1 inhibitors.
Ou-Yang et al. now generated adult conditional BACE1 knockout mice, which allowed them to differentiate between developmental and adult phenotypes. Strikingly, they found that most phenotypes that were observed in germline-deleted BACE1 mice were not observed in the conditional knockouts. This sounds, at first blush, like good news, and may suggest that BACE inhibitors in clinical trials may show little if any substrate-related side effects.
However, Ou-Yang and colleagues still found reduced length and massive disorganization of the hippocampal mossy fiber infrapyramidal bundle in adult BACE1 knockout mice. Moreover, this phenotype was apparently related to the reduction of BACE1-mediated cleavage of the neuronal cell adhesion protein close homolog of L1 (CHL1), which previously was shown to be a BACE1 substrate that is involved in axonal guidance (Dislich et al., 2015; Hitt et al., 2012; Zhou et al., 2012). If a similar phenotype were to be found after treating wild-type mice with BACE1 inhibitors, it would be a warning for clinical trials.
But we are already aware that almost complete inhibition of BACE1 in humans could result in mechanism-based side effects. In a worst-case scenario, efficient BACE1 inhibition could even worsen the clinical outcome of Alzheimer patients.
Furthermore, previous work from our lab also showed that BACE inhibition/knockout induces an alternative pathway for proteolytic processing of APP, which results in the enhanced production of a peptide we have called Aη-α (Willem et al., 2015). This peptide blocked neuronal activity in vivo, a finding that also raises concerns about BACE1 inhibitors and could ultimately worsen cognition in Alzheimer's disease patients. After the rather disastrous, and at least partially predictable, outcome of γ-secretase inhibition in humans, the field would be well advised to carefully address mechanism-based side effects of BACE1 inhibition—and that's exactly what Vassar and colleagues did in a careful and detailed manner.
Dislich B, Wohlrab F, Bachhuber T, Müller SA, Kuhn PH, Hogl S, Meyer-Luehmann M, Lichtenthaler SF. Label-free Quantitative Proteomics of Mouse Cerebrospinal Fluid Detects β-Site APP Cleaving Enzyme (BACE1) Protease Substrates In Vivo. Mol Cell Proteomics. 2015 Oct;14(10):2550-63. Epub 2015 Jul 2 PubMed.
Hitt B, Riordan SM, Kukreja L, Eimer WA, Rajapaksha TW, Vassar R. β-Site Amyloid Precursor Protein (APP)-cleaving Enzyme 1 (BACE1)-deficient Mice Exhibit a Close Homolog of L1 (CHL1) Loss-of-function Phenotype Involving Axon Guidance Defects. J Biol Chem. 2012 Nov 9;287(46):38408-25. PubMed.
Lichtenthaler SF, Lemberg MK, Fluhrer R. Proteolytic ectodomain shedding of membrane proteins in mammals-hardware, concepts, and recent developments. EMBO J. 2018 Aug 1;37(15) Epub 2018 Jul 5 PubMed.
Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, Destrooper B, Saftig P, Birchmeier C, Haass C. Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006 Oct 27;314(5799):664-6. PubMed.
Willem M, Tahirovic S, Busche MA, Ovsepian SV, Chafai M, Kootar S, Hornburg D, Evans LD, Moore S, Daria A, Hampel H, Müller V, Giudici C, Nuscher B, Wenninger-Weinzierl A, Kremmer E, Heneka MT, Thal DR, Giedraitis V, Lannfelt L, Müller U, Livesey FJ, Meissner F, Herms J, Konnerth A, Marie H, Haass C. η-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature. 2015 Oct 15;526(7573):443-7. Epub 2015 Aug 31 PubMed.
Zhou L, Barão S, Laga M, Bockstael K, Borgers M, Gijsen H, Annaert W, Moechars D, Mercken M, Gevaert K, Gevaer K, De Strooper B. The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo. J Biol Chem. 2012 Jul 27;287(31):25927-40. PubMed.View all comments by Christian Haass
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