. Reduced BACE1 activity enhances clearance of myelin debris and regeneration of axons in the injured peripheral nervous system. J Neurosci. 2011 Apr 13;31(15):5744-54. PubMed.

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  1. This work deals with the role of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) in nerve lesions and toxic neuropathies in mice. The enzyme generates the well-known amyloid-β peptide, which is a pathogenetically relevant component of plaques in Alzheimer’s disease (AD) brains, and N-APP, which can trigger axon degeneration. In the present study, the consequences of the absence of BACE1 were investigated in injured peripheral nerves, a topic remote to AD.

    In contrast to axons of the central nervous system (CNS), axons of the peripheral nervous system (PNS) can regrow for long distances after injury. The reasons for this clinically highly relevant difference are manifold and imply neuronal and glial properties. Of particular relevance is the role of a third cell type, nerve-borne and infiltrating macrophages that remove growth-inhibiting myelin from the injured nerve (Vargas and Barres, 2007).

    How might BACE1 relate to peripheral nerve pathology and repair? Initially, the authors might have expected that—due to the absence of the axonopathic BACE1 products—BACE1-deficiency might preserve injured axons. In fact, this was neither the case in the nerve lesion model nor in toxic neuropathy. Instead, the authors observed by in vitro approaches a higher axonal outgrowth rate of BACE1-deficient neurons. Even more spectacular was a substantially increased removal of degenerating myelin and a more robust axonal regrowth and restoration of muscle synapses after nerve injury in the BACE1-deficient mice. Pharmacological inhibition of BACE1 produced similar results as genetic inactivation.

    How might BACE1 deficiency or inhibition improve removal of myelin and axon regrowth? By an in vitro approach, the authors showed that BACE1-deficient macrophages have a higher capacity for phagocytosis, which could lead to an increased removal of myelin, thus “clearing” pathways for axon regrowth. This issue could be further characterized experimentally by testing the increased clearance capacity of BACE1-/- macrophages when transplanting them into normal (i.e., BACE1+) mice before nerve injury.

    The authors’ favored interpretation of increased myelin phagocytosis by macrophages is that the triggering receptor expressed on myeloid cells-2 (TREM-2), a cell surface protein that drives macrophages into a phagocytic activation state (Takahashi et al., 2007), might be a substrate of BACE1: More preserved TREM-2 in the absence of BACE1 could lead to more phagocytosis of myelin. Together with the increased outgrowth properties of BACE1-deficient neurons, the removal of myelin of lesioned fibers may substantially increase axonal regeneration and reinnervation of denervated muscle fibers.

    The study has important therapeutic implications, particularly since regrowth of axons over long distances is clearly a limiting factor of nerve regeneration in humans. Thus, inhibiting BACE1 after nerve injury might be a promising approach to accelerate regeneration and to reduce the risk of denervated organs being irreversably lost by atrophy due to delayed contact with regrown axons. In a more general take-home message, the study indirectly supports the concept of myelin removal as an important prerequisite for axon regrowth. This process is extremely delayed in the CNS and may partially explain the chronically poor outcome of spinal cord injury and other traumata of the CNS (Vargas and Barres, 2007). Thus, it should be a future challenge to investigate BACE1 inhibition in models for CNS injuries.

    All in all, the paper by the Baltimore group around John W. Griffin is a gem with strong therapeutical and conceptual implications. It profoundly extends our knowlege about possible therapeutic intervention cues in nerve injury. The clinical application using existing BACE1 inhibitors originally designed for treatment of AD would honor this and other pivotal work by Jack Griffin, who sadly passed away a few days after the appearence of this paper.

    References:

    . TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med. 2007 Apr;4(4):e124. PubMed.

    . Why is Wallerian degeneration in the CNS so slow?. Annu Rev Neurosci. 2007;30:153-79. PubMed.

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