Endoplasmic Reticulum Stress Induces Tau Pathology and Forms a Vicious Cycle: Implication in Alzheimer's Disease Pathogenesis

Laboratory of Neurodegenerative Diseases, Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 11/2011; 28(4):839-54. DOI: 10.3233/JAD-2011-111037
Source: PubMed


Accumulation of unfolded proteins can disturb the functions of the endoplasmic reticulum (ER), leading to ER-stress or unfolded protein response (UPR). Recent data have shown that activation of UPR can be found in postmortem brains of Alzheimer's disease (AD) patients; and biological markers for activation of UPR are abundant in neurons with diffuse phosphorylated tau. Although these observations suggest a linkage between ER-stress and tau pathology, little is known of their relationship. In this study, we found that high levels of phosphorylated PKR-like ER-resident kinase (p-PERK) and phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) as markers for activation of UPR in the hippocampus of aged P301L mutant tau transgenic mice. The immunoreactivity of p-PERK was found to co-localize with that of phosphorylated tau. We then hypothesized that phosphorylation of tau could induce ER-stress and vice versa in promoting AD-like pathogenesis. By using the protein phosphatase 2A inhibitor okadaic acid (OA) as an inducer for phosphorylation of tau, we found that primary cultures of rat cortical neurons treated with OA triggered UPR as indicated by increased levels of p-PERK and p-eIF2α, splicing of mRNA for xbp-1 and elevated levels of mRNA for GADD153. On the other hand, thapsigargin as an ER-stress inducer stimulated phosphorylation of tau at Thr231, Ser262 and Ser396. Thapsigargin also induced activation of caspase-3 and cleavage of tau. These findings suggested that ER-stress and hyperphosphorylation of tau could be induced by each other to form a vicious cycle to propagate AD-like neurodegeneration.

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    • "Neurons are highly reliant on mitochondrial function since most neuronal ATP is generated through oxidative phosphorylation (Correia et al., 2012). The high-energy demand is dictated by numerous neuronal processes, including axonal transport of macromolecules and organelles, maintenance of membrane potential, buffering cytosolic Ca 2 + , and loading and releasing neurotransmitters into the synaptic cleft, a site distant from the soma (Saxton and Hollenbeck, 2012). These dynamic organelles are generated from the division of pre-existing organelles in the soma—a process called mitochondrial biogenesis—and have a particularly long half-life, increasing the probability of accumulating damage (DuBoff et al., 2013). "
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    • "These eIF2α kinases activate glycogen synthase kinase-3β (GSK-3β), a major tau kinase, in brain (Baltzis et al., 2007; Bose et al., 2011). Furthermore, there is evidence that PERK and PKR may also facilitate phosphorylation of tau independently of GSK-3β connection in some experimental setting (Azorsa et al., 2010; Ho et al., 2012). Of particular interest, Ho et al. (2012) report that ER stress-related activation of the PERK-eIF2α pathway causes tau phosphorylation, while levels of phosphorylated PERK and eIF2α are increased in response to experimentally induced hyperphosphorylation of tau in primary cortical cultures and TauP301L transgenic mice. "
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    • "The UPR may therefore initiate two key aspects of tau pathology by generating abnormally phosphorylated tau species and promoting tau aggregation. In support of this possibility, Ho et al. (2012) demonstrated tau phosphorylation following UPR activation in primary neuronal cultures from rats. "

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