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



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.



Pretangles contained either paired helical filaments (PHFs) or PtdIns(4,5)P2-immunopositive small vesicles (approximately 1 μm 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-3β and spleen tyrosine kinase.



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.
Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
T
T
Nishikawa
Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
T
T
Takahashi
Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
M
M
Nakamori
Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
N
N
Hosomi
Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
H
H
Maruyama
Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of Medicine, University of Tokushima, Tokushima, Japan.
Y
Y
Miyazaki
Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of Medicine, University of Tokushima, Tokushima, Japan.
Y
Y
Izumi
Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
M
M
Matsumoto
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D022162:Cytoplasmic Vesicles / Q000473:pathology / Q000648:ultrastructure*; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000473:pathology / Q000648:ultrastructure*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D000072377:Syk Kinase / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
C054369:MAPT protein, human; D008565:Membrane Proteins; C106354:flotillins; D016875:tau Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C068961:phosphatidylinositol 4,5-biphosphate kinase; C000606896:SYK protein, human; D000072377:Syk Kinase; D000071679:Glycogen Synthase Kinase 3 beta
Alzheimer's disease; granulovacuolar degeneration; lipid raft; pretangle; signaling endosome; tau