Autophagosomes cooperate in the degradation of intracellular C‐terminal fragments of the amyloid precursor protein via the MVB/lysosomal pathway

Abstract

Brain regions affected by Alzheimer disease (AD) display well‐recognized early neuropathologic features in the endolysosomal and autophagy systems of neurons, including enlargement of endosomal compartments, progressive accumulation of autophagic vacuoles, and lysosomal dysfunction. Although the primary causes of these disturbances are still under investigation, a growing body of evidence suggests that the amyloid precursor protein (APP) intracellular C‐terminal fragment β (C99), generated by cleavage of APP by β‐site APP cleaving enzyme 1 (BACE‐1), is the primary cause of the endosome enlargement in AD and the earliest initiator of synaptic plasticity and long‐term memory impairment. The aim of the present study was to evaluate the possible relationship between the endolysosomal degradation pathway and autophagy on the proteolytic processing and turnover of C99. We found that pharmacologic treatments that either inhibit autophagosome formation or block the fusion of autophagosomes to endolysosomal compartments caused an increase in C99 levels. We also found that inhibition of autophagosome formation by depletion of Atg5 led to higher levels of C99 and to its massive accumulation in the lumen of enlarged perinuclear, lysosomal‐associated membrane protein 1 (LAMP1)‐positive organelles. In contrast, activation of autophagosome formation, either by starvation or by inhibition of the mammalian target of rapamycin, enhanced lysosomal clearance of C99. Altogether, our results indicate that autophagosomes are key organelles to help avoid C99 accumulation preventing its deleterious effects.—González, A. E., Muñoz, V. C., Cavieres, V. A., Bustamante, H. A., Cornejo, V.‐H., Januário, Y. C., González, I., Hetz, C., da Silva, L. L., Rojas‐Fernández, A., Hay, R. T., Mardones, G. A., Burgos, P. V. Autophagosomes cooperate in the degradation of intracellular C‐terminal fragments of the amyloid precursor protein via the MVB/lysosomal pathway. FASEB J. 31, 2446–2459 (2017). http://www.fasebj.org

Contribution of the endosomal-lysosomal and proteasomal systems in Amyloid-β Precursor Protein derived fragments processing

“…Treatments with CQ or Baf A1 inhibited β-CTFs degradation and reduced Aβ peptides and sAPPβ production while they increased sAPPα secretion, suggesting that the amyloidogenic pathway was reduced in favour of the α-secretase cleavage. These results are in agreement with previous reports showing that the endosomal/lysosomal pathway is of particular importance for the whole APP processing, and in particular for efficient amyloidogenic processing [14,15,17].…”

“…These intriguing questions remain open and require further investigations. Our results also confirmed that besides being cleaved by γ-secretase, APP-CTFs are efficiently degraded by the endosomal/lysosomal pathway, as it was previously reported [14,15,17]. Along with reducing APP-CTFs degradation, drugs that were used to inhibit the endosomal/lysosomal pathway significantly reduced the secretion of Aβ peptides and sAPPβ species.…”

Trafficking of a multifunctional protein by endosomal microautophagy: linking two independent unconventional secretory pathways

“…A recent report by González et al . (74) has demonstrated a relationship between the endolysosomal degradation pathway and autophagy on the proteolytic processing and turnover of amyloid precursor protein. The authors demonstrated that inhibition of autophagosome formation leads to its massive accumulation in intracellular vesicles.…”

Processing of the SARS-CoV pp1a/ab nsp7–10 region

“…The activity of M pro is regulated over mechanisms comprising maturation from the polyprotein by autoprocessing of nsp4-5 and nsp5-6, as well as concentration and substrate induced self-assembly into an active dimeric unit [12][13][14]. After freeing itself, M pro liberates nsp's 6-16 from the polyprotein by specifically targeting their nsp inter-domain junctions.…”