Jaeger PA, Pickford F, Sun CH, Lucin KM, Masliah E, Wyss-Coray T.
Regulation of amyloid precursor protein processing by the Beclin 1 complex.
PLoS One. 2010;5(6):e11102.
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The results in Jaeger et al. reinforce previous work from their lab (Pickford et al., 2008) showing that autophagy is a significant APP turnover pathway that can be strongly upregulated in cells. During autophagy induction, APP levels decreased somewhat more than Aβ levels, consistent with earlier data that Aβ is generated during autophagy and that efficient lysosomal proteolysis is needed to prevent the intracellular buildup of Aβ in autophagic vacuoles and lysosomes seen in AD. The authors also show that the block in autophagosome clearance in AD and AD mouse models can be exacerbated by beclin deficiency. This may be due to the impairment of early autophagy steps of autophagosome formation, which require beclin, as proposed in the paper, and it could also reflect interference with beclin-dependent late endosome functions, disturbances of which are known to disrupt amphisome formation and clearance through autophagy (1). Interestingly, the resultant buildup of APP and β-CTF in endosomal-related compartments is reminiscent of the conditions that develop in Down syndrome, where it has been shown that APP duplication, through elevations of β-CTF, accelerates endocytosis (2). This creates more substrate traffic to lysosomes, interferes with endosome functions (2,3), and we suspect, also impairs autophagic turnover. These new investigations add to mounting evidence that disruption of lysosomal clearance mechanisms may be a critical factor in AD pathogenesis.
Filimonenko M, Stuffers S, Raiborg C, Yamamoto A, Malerød L, Fisher EM, Isaacs A, Brech A, Stenmark H, Simonsen A.
Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease.
J Cell Biol. 2007 Nov 5;179(3):485-500.
Jiang Y, Mullaney KA, Peterhoff CM, Che S, Schmidt SD, Boyer-Boiteau A, Ginsberg SD, Cataldo AM, Mathews PM, Nixon RA.
Alzheimer's-related endosome dysfunction in Down syndrome is Abeta-independent but requires APP and is reversed by BACE-1 inhibition.
Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1630-5.
Cataldo AM, Mathews PM, Boiteau AB, Hassinger LC, Peterhoff CM, Jiang Y, Mullaney K, Neve RL, Gruenberg J, Nixon RA.
Down syndrome fibroblast model of Alzheimer-related endosome pathology: accelerated endocytosis promotes late endocytic defects.
Am J Pathol. 2008 Aug;173(2):370-84.