Abstract
The spread of neurofibrillary tangle (NFT) pathology through the human brain is a hallmark of Alzheimer’s disease (AD), which is thought to be caused by the propagation of “seeding” competent soluble misfolded tau. “TauC3”, a C-terminally truncated form of tau that is generated by caspase-3 cleavage at D421, has previously been observed in NFTs and has been implicated in tau toxicity. Here we show that TauC3 is found in the seeding competent high molecular weight (HMW) protein fraction of human AD brain. Using a specific TauC3 antibody, we were able to substantially block the HMW tau seeding activity of human AD brain extracts in an in vitro tau seeding FRET assay. We propose that TauC3 could contribute to the templated tau misfolding that leads to NFT spread in AD brains.
Highlights
In addition to its role as an axonal microtubule binding protein, tau is a major constituent of neurofibrillary tangles (NFTs) occurring in Alzheimer’s disease (AD) brains [1,2]
We found that high molecular weight (HMW) tau from human AD brain extracts can seed the aggregation of tau in cells in vitro [4]
To better understand which forms of tau are present in the HMW fraction, we probed western blots of this HMW fraction from human AD brain extract (Table 1) with antibodies recognizing the C-terminus (Tau46, epitope aa404-441) or the N-terminus (Tau13, aa2-18) of full-length tau
Summary
In addition to its role as an axonal microtubule binding protein, tau is a major constituent of neurofibrillary tangles (NFTs) occurring in Alzheimer’s disease (AD) brains [1,2]. Tau undergoes several post-translational modifications, and it is unclear which forms constitute the seed competent species. Soluble high molecular weight (HMW) tau isolated from human AD brain shows seeding bioactivity in in vitro assays [3,4] and contains various truncated and phosphorylated forms of tau. The activation of caspases occurs early in apoptosis and is thought to be involved in the cascade of tau processing that eventually leads to NFT formation[6].
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