Dehydroevodiamine attenuates calyculin A-induced tau hyperphos-phorylation in rat brain slices

Abstract

Aim: This study was to investigate the effect of dehydroevodiamine (DHED) on Alzheimer's disease (AD)-like tau hyperphosphorylation induced by calyculin A (CA), an inhibitor of protein phosphatase (PP)-2A and PP-1, and the involvement of PP-2A in metabolically competent rat brain slices. Methods: Rat brain slices were pre-incubated at 33 °C in the presence (10, 100, and 200 µmol/L, respectively) or absence of DHED for 1 h. Then, CA 0.1 µmol/L was added and the slices were treated for another 2 h. Western blotting and/or immunohistochemistry were used to measure the phosphorylation level of tau and PP-2A. Results: CA treatment could remarkably increase the immunoreactivity of pS262 and decrease the staining of Tau-1, representing tau hyperphosphorylation at Ser262 (pS262) and Ser198/ 199/202 (Tau-1, as the antibody reacts with unphosphorylated tau, therefore, decreased staining represents increased phosphorylation). Pre-incubation of the brain slices with DHED could efficiently attenuate the CA-induced tau hyperphosphorylation at the above AD-related sites. Additionally, DHED also decreased the basal phosphorylation level of tau at Ser396, although CA failed to induce tau hyperphosphorylation at this site. Furthermore, CA treatment induced an increased level of Tyr307-phosphorylated PP-2A, which represents inactivation of the phosphatase, whereas DHED arrested the elevation of the inhibitory modification of PP-2A. Conclusion: DHED can attenuate CA-induced tau hyperphosphorylation at multiple AD-related sites in metabolically active rat brain slices. The underlying mechanism may involve a decreased inhibitory phosphorylation of PP-2A at Tyr307.

Correcting miR92a-vGAT-Mediated GABAergic Dysfunctions Rescues Human Tau-Induced Anxiety in Mice

“…5,6,42 In AD patients, tau pathologies start to appear from entorhinal cortex and then spread to hippocampal limbic regions. 16,17 In previous studies, we invariably observe that tau pathology appears most apparent and early in CA3 compared with the other regions in htau-transgenic mice 21 or the rats exposed to calyculin A 18 or to advanced glycation end products (AGEs), 19 suggesting that hippocampal CA3 may be more vulnerable to tauopathies. The hippocampus formation, consisting of CA1, CA2, CA3, CA4, and dentate gyrus, is crucial in maintaining normal cognitive functions and the emotional state.…”

“…16,17 In our previous studies, we consistently observe that hippocampus CA3 subset seems most vulnerable to tau hyperphosphorylation and accumulation. [18][19][20][21] However, how these peculiar tau pathologies link to the behavioral alterations is not fully understood.…”

Anti-inflammatory and anti-infectious effects of Evodia rutaecarpa (Wuzhuyu) and its major bioactive components

“…In rat brain slices, DeHE attenuated calyculin A, a protein phosphatase (PP)-2A and PP-1inhibitor, and induced Alzheimer's disease-like tau hyperphosphorylation [68]. Evodia officinalis extract demonstrated the most protective effects among 10 kinds of plant extracts against the carboxy-terminal 105 amino acid fragments of amyloid precursor protein induced neurotoxicity [69].…”

Dehydroevodiamine·HCl enhances cognitive function in memory-impaired rat models

“…DHED is protective against immobilization stress-induced memory deficit and behavioral impairment [32]. DHED inhibits calyculin A-induced tau in AD-like rat brain slices [19]. Moreover, DHED decreases tau hyperphosphorylation and spatial memory impairment [16].…”

“…Antiamnestic effects of DHED occur through an improvement of learning and memory and an inhibition of neuronal dysfunction in a scopolamine-induced amnesic rat model [1819]. Furthermore, DHED has hypotensive and neuroprotective effects and modulates nitric oxide production [2021].…”