Analysis of isoform-specific tau aggregates suggests a common toxic mechanism involving similar pathological conformations and axonal transport inhibition

NEUROBIOLOGY OF AGING

卷:47

Article

Cox, Kristine^1,2,3  Combs, Benjamin^1,2  Abdelmesih, Brenda²  Morfini, Gerardo^2,4  Brady, Scott T.^2,4  Kanaan, Nicholas M.^1,5,6 

[1] Michigan State Univ, Coll Human Med, Dept Translat Sci & Mol Med, 333 Bostwick Ave NE, Grand Rapids, MI 49503 USA

[2] Marine Biol Lab, Woods Hole, MA 02543 USA

[3] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA

[4] Univ Illinois, Dept Anat & Cell Biol, Chicago, IL USA

[5] Michigan State Univ, Neurosci Program, E Lansing, MI 48824 USA

[6] Mercy Hlth St Marys, Hauenstein Neurosci Ctr, Grand Rapids, MI USA

关键词: Tauopathy;    Alzheimer's disease;    Oligomer;    Axon;    Aggregation;    Microtubule-associated protein;    Pathological conformations;   

DOI  :  10.1016/j.neurobiolaging.2016.07.015

来源: Elsevier

【 摘 要 】

Misfolded tau proteins are characteristic of tauopathies, but the isoform composition of tau inclusions varies by tauopathy. Using aggregates of the longest tau isoform (containing 4 microtubule-binding repeats and 4-repeat tau), we recently described a direct mechanism of toxicity that involves exposure of the N-terminal phosphatase-activating domain (PAD) in tau, which triggers a signaling pathway that disrupts axonal transport. However, the impact of aggregation on PAD exposure for other tau isoforms was unexplored. Here, results from immunochemical assays indicate that aggregation-induced increases in PAD exposure and oligomerization are common features among all tau isoforms. The extent of PAD exposure and oligomerization was larger for tau aggregates composed of 4-repeat isoforms compared with those made of 3-repeat isoforms. Most important, aggregates of all isoforms exhibited enough PAD exposure to significantly impair axonal transport in the squid axoplasm. We also show that PAD exposure and oligomerization represent common pathological characteristics in multiple tauopathies. Collectively, these results suggest a mechanism of toxicity common to each tau isoform that likely contributes to degeneration in different tauopathies. (C) 2016 The Author(s). Published by Elsevier Inc.

【 授权许可】

Free