Year: 2010
Type: article
Abstract: The microtubule (MT)-associated protein tau is implicated in many neurodegenerative diseases and serves as a pathologic hallmark in Alzheimer's disease. It has been shown recently that accumulation of the amyloid ß 1-42 peptide (Aß) is required to precipitate tau dysfunction in Alzheimer's, but how this occurs is unknown. One possibility would be simply based on the deleterious pluripotency of Aß; the extracellular accumulation of this sticky protein affects a number of pathways, and it is the combination of these deregulatory events that initiates tau pathogenesis. It has been shown that Aß can cause both aberrant MT disruption and activation of various kinase pathways leading to tau hyper-phosphorylation. Here, we have tested what impact these events have on the interaction of tau with molecular chaperones. We have used cell culture and recombinant protein techniques to investigate specific mechanisms of tau regulation. We have found that very soon after MT destabilization, endogenous tau is bound by molecular chaperones, and at this point its fate can be dictated by chemical regulators of these chaperones. Moreover, we show that these chaperones can either facilitate or prevent tau folding into the conformation known as MC1, which is thought to be an early event during the progression of Alzheimer's disease pathology. Interestingly, in our model, MC1 formation precedes tau phosphorylation, and perhaps more importantly, tau hyper-phosphorylation actually prevents MC1 formation, but enhances chaperone binding. Chaperones may be serving as unwitting vectors that preserve tau, whether good or bad. It also suggests that once tau falls from the MTs in a disordered or aberrant fashion, it is immediately bound by chaperones and folded to prevent its exposed hydrophobic domains from aggregating; however when MT destabilization is accompanied by kinase activation, chaperone binding goes up, but tau folding is blocked, allowing tau to be preserved in a linear, but hyper-phosphorylated state that may be more aggregation-competent. Thus, the pleiotropic activities of Aß may simultaneously converge to overcome protective strategies evolved by the neuron to deal with misfolded proteins. Therapies aimed at disrupting the chaperone/tau interface may be highly relevant for treating AD at the stage where tau dysfunction has initiated.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2079849239