Journal
JOURNAL OF PINEAL RESEARCH
Volume 67, Issue 1, Pages -Publisher
WILEY
DOI: 10.1111/jpi.12578
Keywords
Alzheimer's disease; autophagy; cognitive decline; melatonin; tau
Categories
Funding
- Spanish Ministry of Economy and Competence [SAF2015-63935R]
- Comunidad Autonoma de Madrid [B2017/BMD-3827]
- European Regional Development's funds (FEDER) [CP16/00014]
- Spanish Ministry of Health (Instituto de Salud Carlos III) [PI17/01700]
- Fundacion la Caixa [CI17-00048]
Ask authors/readers for more resources
Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV-hTau(P301L) viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau-related models. Melatonin (10 mu mol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV-hTau(P301L) increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase-3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available