Granular Tau Oligomers as Intermediates of Tau Filaments

TLDR

Neurofibrillary tangles, composed of tau protein forming paired helical and straight filaments, are hallmark lesions in Alzheimer’s disease and other neurodegenerative disorders. The study aims to determine whether reducing granular tau aggregates could serve as a therapeutic strategy for tauopathies and promote healthy brain aging. Atomic force microscopy, CD spectroscopy, and immunostaining revealed that granular tau aggregates precede filament formation, are elevated in early Braak stages, and may serve as an early diagnostic marker for tauopathy.

Abstract

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.