Poul Henning Jensen, Denmark
Aarhus University DANDRITE, BiomedicineAuthor Of 1 Presentation
PKR KINASE DIRECTLY REGULATES TAU EXPRESSION AND ALZHEIMER'S DISEASE-RELATED TAU PHOSPHORYLATION
Abstract
Aims
Deposition of extensively hyperphosphorylated tau in specific brain cells is a clear pathological hallmark in Alzheimer’s disease and other tauopathies. Furthermore, the well-established “tau hypothesis” postulate that hyperphosphorylation of tau abolishes its microtubule-stabilizing role, and leaves it vulnerable to self-assembly, thereby promoting neuronal dysfunction and death. This suggests a central role of hyperphosphorylation in tauopathies, but so far no disease-causing kinase has been identified. Here we investigate the relationship between acute encephalitis, activation of the inflammation/infection-activated kinase, PKR, and pathological tau phosphorylation.
Methods
PKRs role in tau phosphorylation was assessed via in vitro phosphorylation assays, cellular overexpression of constitutively active PKR, and PKR inhibition in rTg4510 mice brain slices, using specific phospho-tau antibodies. qPCR and microtubule-binding assays were also performed. Finally, to induce acute encephalopathy, robust inflammation, and PKR upregulation, Langat virus was intracranial injected in wild-type mice.
Results
We observe that PKR directly phosphorylates numerous abnormal and disease-modifying residues within tau including Thr181, Ser199/202, Thr231, Ser262, Ser396, Ser404 and Ser409. Similar, we find that these phosphorylations actively displace cellular tau from microtubules. In addition, PKR overexpression and knockdown, respectively, increase and decrease tau protein and mRNA levels in cells. Finally, acute encephalopathy induces robust inflammation and PKR upregulation, accompanied by abnormally phosphorylated full-length- and truncated tau.
Conclusions
These findings indicate that PKR, independent of other kinases, and upon acute brain inflammation, capably trigger pathological modulation of tau, which in turn, might form the initial pathologic seed in several tauopathies such as Alzheimer’s disease and Chronic traumatic encephalopathy where inflammation is severe.