Description
Modulation of Inflammation and Autophagy as a Therapeutic Strategy for the Treatment of Alzheimer's Disease
Buendia I.1,2, Luengo E.1, Fernández-Mendívil1, Trigo P.1, Michalska P.1, León R.1,2
López MG1,2,*
1Instituto Teófilo Hernando (ITH). Universidad Autónoma de Madrid, España; 2Departmento de farmacología de la Facultad de Medicina. Universidad Autónoma de Madrid, España; 3 Hospital Universitario de la Princesa
It is widely known that in patients with Alzheimer´s Disease (AD), the main histopathological feature is the proteinopathy along with an increase in oxidative stress and neuroinflammation. Nowadays, it has been proven a strong correlation between the load and distribution of hyperphosphorylated tau protein and cognitive decline in AD patients. On the other hand, although previous studies have shown that autophagy is impaired in AD, neither the mechanisms underlying this process have been elucidated nor whether its modulation could be a novel therapeutic strategy.
The aims of this study have been: (i) to understand the relationship between hyperphosphorylation of tau protein, neuroinflammation and alteration of autophagy in different in vivo models of tauopathy (ii) to assess the potential neuroprotective effects of late melatonin treatment in this tauopathy model and its potential relation with autophagy.
In this work, we have demonstrated that melatonin treatment improves tauopathy in different ex vivo, in vivo and human models by modulating autophagy. The intracerebroventricular injection (i.c.v) of AAV-hTau (1011 VP) or the PP2A inhibitor okadaic acid injection in mice generates inflammation, oxidative stress and autophagy impairment 7 days after its injection (dai), without displaying any cognitive decline. Nevertheless, 28 days post injection (dpi), in addition to the alterations described above, AAV-hTau injected mice manifest severe cognitive deficit, indicating that inflammation, oxidative stress and autophagy disruption are previous events to the memory loss. Nowadays, neuroinflammation, oxidative stress and altered autophagy are thought to underlie most neurodegenerative diseases, such as AD, in which the recovery of these alterations are being highly investigated as therapeutic targets. In this line, melatonin not only restores hypherphosphorylation of Tau protein, oxidative stress and neuroinflammation, but also restores autophagic alteration, which is inhibited due to the hyperphosphorylation of Tau protein not only in in vivo, but also in newly developed human tauopathy model. These results allow us to propose that the restoration of autophagy levels and inflammation by melatonin could be of interest as treatment of AD.
Funding: Thanks to the Spanish ministry grant “SAF 2015-63935-R” to López MG. and to the continuous support of Instituto Teófilo Hernando and Instituto La Princesa.