Granular tau oligomers as intermediates of tau filaments.
Neurofibrillary tangles (NFTs) are pathological hallmarks of several neurodegenerative disorders, including Alzheimer's disease (AD). NFTs are composed of microtubule-binding protein tau, which assembles to form paired helical filaments (PHFs) and straight filaments. Here we show by atomic force microscopy that AD brain tissue and in vitro tau form granular and fibrillar tau aggregates. CD spectral analysis and immunostaining with conformation-dependent antibodies indicated that tau may undergo conformational changes during fibril formation. Enriched granules generated filaments, suggesting that granular tau aggregates may be an intermediate form of tau fibrils. The amount of granular tau aggregates was elevated in prefrontal cortex of Braak stage I cases compared to that of Braak stage 0 cases, suggesting that granular tau aggregation precedes PHF formation. Thus, granular tau aggregates may be a relevant marker for the early diagnosis of tauopathy. Reducing the level of these aggregates may be a promising therapy for tauopathies and for promoting healthy brain aging.
Maeda
Sumihiro
S
Lab for Alzheimer's Disease, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Sahara
Naruhiko
N
Saito
Yuko
Y
Murayama
Miyuki
M
Yoshiike
Yuji
Y
Kim
Hyonchol
H
Miyasaka
Tomohiro
T
Murayama
Shigeo
S
Ikai
Atsushi
A
Takashima
Akihiko
A
D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000737:chemistry / Q000378:metabolism; D001923:Brain Chemistry; D002942:Circular Dichroism; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018625:Microscopy, Atomic Force; D016874:Neurofibrillary Tangles / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D016875:tau Proteins