☆ 4.5 Article

The identification of raft-derived tau-associated vesicles that are incorporated into immature tangles and paired helical filaments

NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY (2016)

Journal

NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY

Volume 42, Issue 7, Pages 639-653

Publisher

WILEY

DOI: 10.1111/nan.12288

Keywords

Alzheimer's disease; granulovacuolar degeneration; lipid raft; pretangle; signaling endosome; tau

Funding

Japanese Ministry of Education, Culture, Sports, Science, and Technology
Merck Sharp and Dohme (MSD) K. K., Tokyo, Japan
Smoking Research Foundation, Tokyo, Japan
Grants-in-Aid for Scientific Research [26293211] Funding Source: KAKEN

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Abstract

Aims: Neurofibrillary tangles (NFTs), a cardinal pathological feature of neurodegenerative disorders, such as Alzheimer's disease (AD) are primarily composed of hyper-phosphorylated tau protein. Recently, several other molecules, including flotillin-1, phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] and cyclin-dependent kinase 5 (CDK5), have also been revealed as constituents of NFTs. Flotillin-1 and PtdIns(4,5) P2 are considered markers of raft microdomains, whereas CDK5 is a tau kinase. Therefore, we hypothesized that NFTs have a relationship with raft domains and the tau phosphorylation that occurs within NFTs. Methods: We investigated six cases of AD, six cases of other neurodegenerative diseases with NFTs and three control cases. We analysed the PtdIns(4,5)P2-immunopositive material in detail, using super-resolution microscopy and electron microscopy to elucidate its pattern of expression. We also investigated the spatial relationship between the PtdIns(4,5)P2-immunopositive material and tau kinases through double immunofluorescence analysis. Results: Pretangles contained either paired helical filaments (PHFs) or PtdIns(4,5)P2-immunopositive small vesicles (approximately 1 mu m in diameter) with nearly identical topology to granulovacuolar degeneration (GVD) bodies. Various combinations of these vesicles and GVD bodies, the latter of which are pathological hallmarks observed within the neurons of AD patients, were found concurrently in neurons. These vesicles and GVD bodies were both immunopositive not only for PtdIns(4,5)P2, but also for several tau kinases such as glycogen synthase kinase-3 beta and spleen tyrosine kinase. Conclusions: These observations suggest that clusters of raft-derived vesicles that resemble GVD bodies are substructures of pretangles other than PHFs. These tau kinase-bearing vesicles are likely involved in the modification of tau protein and in NFT formation.

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The proteome of granulovacuolar degeneration and neurofibrillary tangles in Alzheimer's disease

David C. Hondius, Frank Koopmans, Conny Leistner, Debora Pita-Illobre, Regina M. Peferoen-Baert, Fenna Marbus, Iryna Paliukhovich, Ka Wan Li, Annemieke J. M. Rozemuller, Jeroen J. M. Hoozemans, August B. Smit

Summary: This study provides a comprehensive assessment of protein abundances in neurons with granulovacuolar degeneration (GVD) and those bearing neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) patients. The research revealed significant changes in protein composition in GVD and tangle-bearing neurons, with proteins related to protein folding, proteasomal function, endolysosomal pathway, and microtubule function being affected in GVD neurons. The study suggests that GVD is part of a pre-NFT stage in AD pathogenesis and may disrupt proteostasis and cellular homeostasis.

ACTA NEUROPATHOLOGICA (2021)