Amyloid ?-peptides interfere with mitochondrial preprotein import competence by a coaggregation process.

ABSTRACT: A? peptides play a central role in the etiology of Alzheimer disease (AD) by exerting cellular toxicity correlated with aggregate formation. Experimental evidence has shown intraneuronal accumulation of A? peptides and interference with mitochondrial functions. Nevertheless, the relevance of intracellular A? peptides in the pathophysiology of AD is controversial. Here we found that the two major species of A? peptides, in particular A?42, exhibited a strong inhibitory effect on the preprotein import reactions essential for mitochondrial biogenesis. However, A? peptides interacted only weakly with mitochondria and did not affect the inner membrane potential or the structure of the preprotein translocase complexes. A? peptides significantly decreased the import competence of mitochondrial precursor proteins via an extramitochondrial coaggregation mechanism. Coaggregation and import inhibition were significantly stronger for the longer peptide A?42, correlating with its importance in AD pathology. Our results demonstrate that direct interference of aggregation-prone A? peptides with mitochondrial protein biogenesis represents a crucial aspect of the pathobiochemical mechanisms contributing to cellular damage in AD.

SUBMITTER: Cenini G 

PROVIDER: S-EPMC5170859 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature