lzheimer?s disease (AD) is characterized by the accumulation of intracellular neurofibrillary tangles (NFTs) composed of
insoluble aggregates of the microtubule-associated protein tau. Tau aggregates have been hypothesized to cause neurotoxicity
based on the spaciotemporal correlation of NFTs with cognitive decline. Though the precise mechanism of neurotoxicity remains
to be elucidated, one potential mechanism is via the disruption of microtubule-dependent axonal transport. Current evidence
indicates that neuronal dysfunction actually precedes the formation of insoluble NFTs, suggesting that prefibrillar aggregates
may in fact be the toxic species. Recent work from the Binder and Brady laboratories focuses on characterizing prefibrillar tau
aggregates as well as strategies to prevent their toxicity. Using a tau oligomer selective antibody, we demonstrate that prefibrillar
tau oligomers are present in markedly elevated quantities in AD and that these aggregates precede the formation of AD pathology.
Using the squid axoplasm model, we provide compelling evidence that inhibition of anterograde fast axoplasmic transport is
a mechanism of tau oligomer-mediated toxicity. This inhibition is likely caused by a conformational change occurring in tau
oligomers that results in the exposure of the phosphatase activation domain (PAD) of tau located at the extreme N-terminus.
Our collective laboratories have demonstrated that the aberrant exposure of PAD results in the activation of a GSK-3 mediated
pathway that causes kinesin to release its cargo. Interestingly, the molecular chaperone Hsp70 can preferentially bind tau
oligomers to prevent this inhibition of transport. Thus, modulation of molecular chaperones provides a potential mechanism for
the prevention of tau oligomer-mediated toxicity.
Kristina Patterson completed her Ph.D in Cell and Molecular Biology at Northwestern University in 2011. She is currently working on the completion
of her MD at Northwestern University?s Feinberg School of Medicine
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