O4‐04‐08: Neuronal tau‐specific stress induction of molecular chaperones: The failure of a coping mechanism
Year: 2011
Type: article
Abstract: The two main pathological hallmarks of Alzheimer'sdisease (AD) share a common seeding phenomenon erupted by protein misfolding and subsequent aggregation. The chaperone family of heat shock proteins is capable of identifying misfolded clients such as hyperphospho-tau and sorts the client's fate for degradation or refolding. Therefore, chaperone-mediated eradication of pathogenic tau could lead to therapeutics of tauopathies like AD. To understand the relationship between tau misfolding and chaperone activation, we sought to 1) identify the impact of tau-induced stress on the expression of chaperones in neurons, 2) elucidate if chaperone levels are altered in rTg4510 tautransgenic mice, 3) address whether the chaperone system is unfit to cope with tau-independent stress induction in rTg4510 brains, and 4) determine if changes to the chaperome are ascribed to soluble or insoluble tau present in rTg4510 mice. Changes to the chaperome were assessed in primary neurons and brains of rTg4510 and control mice by microarrays and immunoblotting techniques. Brain slices of rTg4510 and control mice were subjected to induction of a stress response, and changes to the chaperome were determined by western blot. Finally, immunoblotting of dox-treated rTg4510 brains helped clarify if changes to the chaperome were due to the prevalence of soluble or insoluble tau species. We identified chaperones whose expression was altered in rTg4510 primary neurons and brains. Hsp70 and Hsp27 expression levels opposed each other in both models. We also found that the chaperone system was incompetent at coping with stress responses in rTg4510 mice. This effect was evident, yet less prevalent, in rTg4510 mice where soluble tau was the primary tau species present. We identified protagonists of the tau-specific stress response in neurons. Changes in the expression and protein levels of chaperones suggest that there is specificity within the chaperome to deal with tau stress, and that these mechanisms are overridden by the pathology. This roster of chaperones will help delineate potential mechanisms with which the neuron attempts to cope with tau misfolding. Enhancement of misfolded tau clearance as well as inhibition of tau aggregation pathways will result in therapeutic strategies for tauopathies.
Source: Alzheimer s & Dementia
Authors: Jose Abisambra, Ashley Cannon, John O'Leary, Sarah Brady, Adriana Espinosa, Umesh Jinwal, John Koren, Laura Blair, Jada Lewis, Chad Dickey
Language: English
Topic: Heat shock proteins research
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W1964773183