Macroautophagy impairment plays a key role in sporadic Alzheimer's disease (sAD) neurodegenerative process. Nevertheless, the mechanism(s) that lead to a deficiency in macroautophagy in AD remains elusive. In this work, we identify, for the first time that Beclin-1 acetylation status is implicated in the alterations in autophagy observed in AD neurodegeneration. We observed that Beclin-1 is deacetylated by sirtuin 1 (SIRT1) and acetylated by p300. In addition, Beclin-1 acetylation inhibits autophagosome maturation, leading to impairment in autophagic flux. We also analyzed some proteins known to be involved in the maturation of autophagosomes such as Rab7, which participates in the fusion step with lysosomes. We observed that increased expression of Rab7 might represent a response to boost the formation of large perinuclear lysosome clusters in accordance with an increase in lysosomal biogenesis determined by increase in LAMP-2A, LAMP-1, and cathepsin D expression in AD cells. Thus, our data provides strong evidences that Beclin-1 acetylation impairs the autophagic flux, and despite lysosomal biogenesis seems to be triggered as a compensatory response, autophagosome fusion with lysosomes is compromised contributing to AD neurodegeneration.
Keywords: Acetylation; Alzheimer’s disease; Autophagy; Beclin-1; Sirtuin 1; p300.