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Melatonin Mitigates Kainic Acid-Induced Neuronal Tau Hyperphosphorylation and Memory Deficits through Alleviating ER Stress.

ABSTRACT: Kainic acid (KA) exposure causes neuronal degeneration featured by Alzheimer-like tau hyperphosphorylation and memory deficits. Melatonin (Mel) is known to protect hippocampal neurons against KA-induced damage. However, the underlying mechanisms remain elusive. In the current study, we investigated the protective effect of melatonin on KA-induced tau hyperphosphorylation by focusing on endoplasmic reticulum (ER) stress-mediated signaling pathways. By using primary hippocampal neurons and mouse brain, we showed that KA treatment specifically induced ER stress and activated GSK-3β and CDK5, two major kinases responsible for tau phosphorylation. Inhibition of ER stress efficiently inactivated GSK-3β and CDK5. Mechanistically, we found that KA-induced ER stress significantly activated calpain, a calcium-dependent protease. Inhibition of ER stress or calpain leads to the reduction in KA-induced GSK-3β and CDK5 activities and tau phosphorylation. Moreover, GSK-3β or CDK5 inhibition failed to downregulate ER stress efficiently, suggesting that ER stress functions upstream of GSK-3β or CDK5. Notably, our results revealed that melatonin acts against KA-induced neuronal degeneration and tau hyperphosphorylation via easing ER stress, further highlighting the protective role of melatonin in the KA-induced neuronal defects.

SUBMITTER: Shi C

PROVIDER: S-EPMC5787934 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Active Caspase-6 (Casp6) and Tau cleaved by Casp6 at amino acids 402 (Tau∆D402) and 421 (Tau∆D421) are present in early Alzheimer disease intraneuronal neurofibrillary tangles, which are made primarily of filamentous Tau aggregates. To assess whether Casp6 cleavage of Tau contributes to Tau pathology and Casp6-mediated age-dependent cognitive impairment, we generated transgenic knock-in mouse models that conditionally express full-length human Tau (hTau) 0N4R only (CTO) or together with human Casp6 (hCasp6) (CTC). Region-specific hippocampal and cortical hCasp6 and hTau expression were confirmed with western blot and immunohistochemistry in 2-25-month-old brains. Casp6 activity was confirmed with Tau∆D421 and Tubulin cleaved by Casp6 immunopositivity in 3-25-month-old CTC, but not in CTO, brains. Immunoprecipitated Tau∆D402 was detected in both CTC and CTO brains, but was more abundant in CTC brains. Intraneuronal hippocampal Tau hyperphosphorylation at S202/T205, S422, and T231, and Tau conformational change were absent in both CTC and CTO brains. A slight accumulation of Tau phosphorylated at S396/404 and S202 was observed in Cornu Ammonis 1 (CA1) hippocampal neuron soma of CTC compared to CTO brains. Eighteen-month-old CTC brains showed rare argentophilic deposits that increased by 25 months, whereas CTO brains only displayed them sparsely at 25 months. Tau microtubule binding was equivalent in CTC and CTO hippocampi. Episodic and spatial memory measured with novel object recognition and Barnes maze, respectively, remained normal in 3-25-month-old CTC and CTO mice, in contrast to previously observed impairments in ACL mice expressing equivalent levels of hCasp6 only. Consistently, the CTC and CTO hippocampal CA1 region displayed equivalent dendritic spine density and no glial inflammation. Together, these results reveal that active hCasp6 co-expression with hTau generates Tau cleavage and rare age-dependent argentophilic deposits but fails to induce cognitive deficits, neuroinflammation, and Tau pathology.

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Melatonin Mitigates Kainic Acid-Induced Neuronal Tau Hyperphosphorylation and Memory Deficits through Alleviating ER Stress.

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