. A small-molecule enhancer of autophagy decreases levels of Abeta and APP-CTF via Atg5-dependent autophagy pathway. FASEB J. 2011 Jun;25(6):1934-42. PubMed.

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  1. The findings of Tian and colleagues add to the growing appreciation of autophagy as a pathway that is critical to the clearance of APP and its metabolites and that is disrupted in AD (1,2). As such, autophagy is an attractive target for disease modulation in AD and other neurodegenerative disorders, as shown by promising therapeutic effects of either inducing autophagy with rapamycin in several model systems, or of reversing defective lysosomal proteolytic clearance of autophagy substrates, which is believed to underlie autophagic failure in AD (reviewed in 3). The new findings by the Greengard group are particularly interesting because the SMER28 agent appears to be acting at an unusual, albeit unidentified, site within autophagy. That site is Atg5-dependent but downstream of beclin1 and Ulk1. SMER28 effects are also sensitive to bafilomycin, which may implicate an action on autophagosome-lysosome fusion, as suggested by the authors, but could also indicate effects on autolysosomal proteolysis since baf1 inhibits lysosomal acidification. Modulating either of these steps would target the primary autophagic clearance deficit in AD and may have advantages over stimulating autophagy induction.

    In this regard, autophagic vacuoles (AVs) are among the cellular compartments most enriched in γ-secretase activity (1). Given that APP is an autophagy substrate (2), autophagy stimulation in the presence of a downstream clearance block in individuals with AD may risk generating Aβ or APPβ C-terminal fragments within robustly accumulating AVs. Those AVs would become ineffective in degrading these metabolites and other autophagy substrates in the AD brain. Our recent report (4) provides genetic proof of principle that a highly selective remediation of lysosomal proteolytic deficits in an animal model of AD can have significant therapeutic effects on pathology and cognition. It will be very interesting, therefore, to know more precisely the mechanism of action of SMER28 and whether the SMER28 compound promotes clearance of Aβ/βCTF and other proteins and is therapeutic in AD models in vivo.

    References:

    . Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. J Cell Biol. 2005 Oct 10;171(1):87-98. PubMed.

    . The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest. 2008 Jun;118(6):2190-9. PubMed.

    . Autophagy failure in Alzheimer's disease-locating the primary defect. Neurobiol Dis. 2011 Jul;43(1):38-45. PubMed.

    . Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits. Brain. 2011 Jan;134(Pt 1):258-77. PubMed.