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A small-molecule enhancer of autophagy decreases levels of Abeta and APP-CTF via Atg5-dependent autophagy pathway.

ABSTRACT: The hallmarks of Alzheimer's disease are the aggregates of amyloid-? (??) peptide and tau protein. Autophagy is one major cellular pathway leading to the removal of aggregated proteins. We examined the possibility of inducing autophagy to reduce A? peptide and the amyloid precursor protein (APP)-derived fragment APP-CTF levels in cell lines and primary neuronal cultures. We found that induction of autophagy either by small-molecule enhancers of rapamycin (SMER)28, a small-molecule enhancer of autophagy, or following starvation greatly decreased the levels of A? peptide (apparent EC(50) of ?10 ?M) and APP-CTF (apparent EC(50) of ?20 ?M) in a ?-secretase-independent manner. Pharmacological inhibition of autophagy led to a significant accumulation of A? peptide and APP-CTF and diminished the effect of SMER28. Three essential components of the autophagic pathway, autophagy-related protein (Atg)5, Beclin1, and Ulk1, were shown to be involved in the degradation of A? and APP-CTF, and Atg5 was necessary for the effect of SMER28. In addition, the autophagic marker light chain 3-II cocompartmentalized with APP-CTF. These results support the involvement of autophagy in the clearance of A? and APP-CTF. We therefore propose that small molecule enhancers of autophagy, such as SMER28, may have therapeutic potential for the treatment of Alzheimer's disease and other proteinopathies.

SUBMITTER: Tian Y

PROVIDER: S-EPMC3101026 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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A small-molecule enhancer of autophagy decreases levels of Abeta and APP-CTF via Atg5-dependent autophagy pathway.

Tian Yuan Y Bustos Victor V Flajolet Marc M Greengard Paul P

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20110302 6

The hallmarks of Alzheimer's disease are the aggregates of amyloid-β (Αβ) peptide and tau protein. Autophagy is one major cellular pathway leading to the removal of aggregated proteins. We examined the possibility of inducing autophagy to reduce Aβ peptide and the amyloid precursor protein (APP)-derived fragment APP-CTF levels in cell lines and primary neuronal cultures. We found that induction of autophagy either by small-molecule enhancers of rapamycin (SMER)28, a small-molecule enhancer of au ...[more]

PMID: 21368103

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Project description:The amyloid ?-peptide (A?) of Alzheimer's disease (AD) is generated by proteolysis within the transmembrane domain (TMD) of a C-terminal fragment of the amyloid ? protein-precursor (APP CTF?) by the ?-secretase complex. This processing produces A? ranging from 38 to 49 residues in length. Evidence suggests that this spectrum of A? peptides is the result of successive ?-secretase cleavages, with endoproteolysis first occurring at the ? sites to generate A?48 or A?49, followed by C-terminal trimming mostly every three residues along two product lines to generate shorter, secreted forms of A?: the primary A?49-46-43-40 line and a minor A?48-45-42-38 line. The major secreted A? species are A?40 and A?42, and an increased proportion of the longer, aggregation-prone A?42 compared to A?40 is widely thought to be important in AD pathogenesis. We examined TMD substrate determinants of the specificity and efficiency of ? site endoproteolysis and carboxypeptidase trimming of CTF? by ?-secretase. We determined that the C-terminal negative charge of the intermediate A?49 does not play a role in its trimming by ?-secretase. Peptidomimetic probes suggest that ?-secretase has S1', S2', and S3' pockets, through which trimming by tripeptides may be determined. However, deletion of residues around the ? sites demonstrates that a depth of three residues within the TMD is not a determinant of the location of endoproteolytic ? cleavage of CTF?. We also show that instability of the CTF? TMD helix near the ? site significantly increases endoproteolysis, and that helical instability near the carboxypeptidase cleavage sites facilitates C-terminal trimming by ?-secretase. In addition, we found that CTF? dimers are not endoproteolyzed by ?-secretase. These results support a model in which initial interaction of the array of residues along the undimerized single helical TMD of substrates dictates the site of initial ? cleavage and that helix unwinding is essential for both endoproteolysis and carboxypeptidase trimming.

Dataset Information

A small-molecule enhancer of autophagy decreases levels of Abeta and APP-CTF via Atg5-dependent autophagy pathway.

Publications

A small-molecule enhancer of autophagy decreases levels of Abeta and APP-CTF via Atg5-dependent autophagy pathway.

Similar Datasets

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