. BACE1 Regulates Proliferation and Neuronal Differentiation of Newborn Cells in the Adult Hippocampus in Mice. eNeuro. 2018 Jul-Aug;5(4) Epub 2018 Aug 3 PubMed.


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  1. This is an interesting paper adding to our understanding of physiological BACE1 functions. It demonstrates that BACE1 controls neuronal differentiation. This study is different from a previous paper by Riqiang Yan (Hu et al., 2013) in that it now analyzes adult hippocampal neurogenesis (AHN), which is linked to life-long learning and may be impaired in AD.

    Full BACE1 inhibition—as shown in this paper—would also impair AHN and should obviously be avoided by therapeutic BACE inhibition. However, the study also demonstrates that heterozygous BACE1 KO mice have no defect in AHN. Thus, while full BACE1 inhibition is not a goal for patients, 50 percent or slightly more appears fully acceptable. And that is exactly what is currently done in the clinical trials with BACE inhibitors. Importantly, for prevention trials it is likely that even less than 50 percent of BACE1 inhibition would be sufficient, which should prevent basically all potential side-effects.

    Going forward, it would be important to repeat this study with a pharmacological BACE1 inhibitor to determine to what extent BACE1 can be inhibited without side effects on AHN. In fact, out of the many phenotypes reported in BACE1-deficient mice, only very few have so far been recapitulated in inhibitor-treated adult mice, in particular muscle-spindle alterations (Cheret et al.,  2013) and spine density and LTP defects (Zhu et al., 2018). Additionally, it would be great to establish which BACE1 substrate contributes to the AHN phenotype. An obvious candidate is Jagged 1, based on the previous study from Riqiang Yan. 

    In summary, this beautiful new study enlarges the spectrum of physiological BACE1 functions. With regard to clinical BACE1 inhibitors, it reinforces the general view in the field that BACE1 inhibition of somewhat more than 50 percent may be acceptable and should not come too close to 100 percent. This is currently achieved in clinical trials and suggests that mechanism-based side effects resulting from BACE1 inhibition may be controlled in patients. 


    . BACE1 regulates hippocampal astrogenesis via the Jagged1-Notch pathway. Cell Rep. 2013 Jul 11;4(1):40-9. PubMed.

    . Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles. EMBO J. 2013 Jun 21; PubMed.

    . Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibition Impairs Synaptic Plasticity via Seizure Protein 6. Biol Psychiatry. 2016 Dec 26; PubMed.

    View all comments by Stefan Lichtenthaler
  2. The findings of Chatila and colleagues in BACE1 knockout mice—namely increased proliferation, decreased neurogenesis, and accumulation of undifferentiated neural precursor cells (NPCs) in the subventricular zone of the adult hippocampal dentate gyrus (DG)—are interesting and potentially important considerations for chronic use of BACE inhibitors in Alzheimer’s disease patients. These results from adult mice are consistent with previous observations of decreased DG neurogenesis (Hu et al., 2013), accumulation of clusters of Doublecortin (Dcx)-positive immature neuronal cells in the sub-pial zone and delayed migration during development of the DG (Hou et al., 2017). Collectively, these results indicate that the abnormalities in neurogenesis in the BACE1 constitutive knockout model, even in the adult, are likely to have arisen from the lack of BACE1 throughout development.

    Whether these observations have a major bearing on possible consequences of inhibiting BACE1 in the mature or the aging brain depends not only on the level of inhibition (current BACE inhibitor trials are targeting ~60-75 percent inhibition) but also whether adult neurogenesis is occurring at an appreciable level in the mature and aging human brain and important for memory. Recent literature highlights the ongoing controversy surrounding this issue (Sorrells et al., 2018; Boldrini et al., 2018), however, if adult hippocampal neurogenesis does not decline dramatically with age, then there is clearly a strong imperative to identify the BACE1 substrate/s involved and develop substrate-sparing inhibitors.


    . BACE1 regulates hippocampal astrogenesis via the Jagged1-Notch pathway. Cell Rep. 2013 Jul 11;4(1):40-9. PubMed.

    . BACE1 Deficiency Causes Abnormal Neuronal Clustering in the Dentate Gyrus. Stem Cell Reports. 2017 Jul 11;9(1):217-230. Epub 2017 Jun 29 PubMed.

    . Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature. 2018 Mar 15;555(7696):377-381. Epub 2018 Mar 7 PubMed.

    . Human Hippocampal Neurogenesis Persists throughout Aging. Cell Stem Cell. 2018 Apr 5;22(4):589-599.e5. PubMed.

    View all comments by Jenny Gunnersen
  3. Chatila and colleagues have identified a role for BACE1 in the regulation of hippocampal neurogenesis in adult mice, raising a new concern regarding the use of BACE inhibitors for the treatment of Alzheimer’s disease. The increase in undifferentiated neural precursor cells (NPCs) seen in the dentate gyri of constitutive BACE1 KO mice adds to the physiological and behavioural changes identified in these mice, which include hypomyelination, axon guidance errors, and alterations in synaptic number and function (Munro et al., 2016). It will be important to identify which BACE1 substrate(s) contribute to this phenotype, including APPα/β as considered by the authors; BACE1 has a number of validated substrates expressed in the adult hippocampus such as seizure-related gene 6 (Sez6), Sez6-like (Pigoni et al., 2016) and CHL1. Additionally, it remains to be determined what the functional effect will be of this increase in undifferentiated cells in the hippocampus.

    It is now essential to determine whether the alterations in neurogenesis observed by Chatila et al. are seen in mature, wild-type mice treated with BACE inhibitors, or whether this phenomenon is at least partly the result of other (e.g. compensatory) changes resulting from constitutive BACE1 KO. This study also reinforces the importance of identifying the optimal level of BACE1 inhibition for the treatment of Alzheimer’s disease which will slow disease progression while minimizing potential side effects. Unlike BACE1 KO mice, BACE1 heterozygous mice show no changes in NPC proliferation and may not have a decrease in neuronal differentiation of NPCs (although, as the authors discuss, this point is not completely clear). Clinically, the most appropriate level of inhibition of BACE1 proteolytic activity remains to be determined, although complete inhibition is not the aim.

    Past animal studies have shown that BACE inhibition can result in changes to dendritic spine plasticity (Filser et al., 2015; Zhu et al., 2016) and cognitive deficits (Filser et al., 2015). It is important to ascertain any additional mechanism-based side effects of BACE inhibition that could counteract the potential benefits of this treatment strategy, particularly in light of the recent clinical trials of BACE1 inhibitor verubecestat, which had no effect on cognitive decline in patients. Here, Chatila et al. have identified a physiological function of BACE1 that could significantly impact on plasticity and memory function and should be given attention in future studies involving BACE inhibitors.


    . Functions of the Alzheimer's Disease Protease BACE1 at the Synapse in the Central Nervous System. J Mol Neurosci. 2016 Nov;60(3):305-315. Epub 2016 Jul 25 PubMed.

    . Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons. Mol Neurodegener. 2016 Oct 5;11(1):67. PubMed.

    . Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions. Biol Psychiatry. 2015 Apr 15;77(8):729-39. Epub 2014 Oct 29 PubMed.

    . Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibition Impairs Synaptic Plasticity via Seizure Protein 6. Biol Psychiatry. 2016 Dec 26; PubMed.

    View all comments by Kathryn Munro

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  1. Alzheimer’s Disease-Related Proteins Needed for Neurogenesis