. The Alzheimer's β-secretase enzyme BACE1 is required for accurate axon guidance of olfactory sensory neurons and normal glomerulus formation in the olfactory bulb. Mol Neurodegener. 2011;6:88. PubMed.

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  1. This study by Rajapaksha et al. provides novel, very interesting, and important insights to the role of BACE in Neurobiology. Rajapaksha and coauthors applied an elegant genetic approach to explore the role of BACE in the olfactory system. Analysis of BACE-/- mice revealed smaller olfactory bulbs and mistargeted olfactory sensory neurons (OSNs), suggesting that BACE is involved in the process of axonal guidance of OSNs. The data are intriguing and, as the authors state in the paper, it will be interesting to learn whether the neuronal phenotype also impacts olfactory function, whether BACE plays a similar role in other neuronal subtypes, and what are the substrates/signaling pathways involved that cause the phenotype. From other BACE gene targeting studies (1), we have learned that only a limited decrease in BACE activity (BACE+/- mice) is sufficient to affect the development of amyloid pathology. It will therefore be interesting to learn whether the OSN phenotype is also present in BACE+/- mice and, from a drug discovery perspective, whether small molecule-mediated inhibition of BACE, at doses efficacious in lowering Aβ production, has any impact on the sensory neuronal network of the olfactory system.

    References:

    . Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP Transgenic Mice. J Biol Chem. 2007 Sep 7;282(36):26326-34. PubMed.

  2. BACE1 inhibitor developers should take note of this paper by Rajapaksha et al. It is a novel finding that raises valid questions about potential BACE1 inhibitor drugs. Rajapaksha and colleagues looked only into the olfactory system. It's a good start that provided very interesting results; however, investigators should look into effects of BACE1 in more critical areas of the brain.