NOX-4 as therapeutic target for the treatment of Alzheimer´s Disease
Luengo E1, Buendia I1,2, Trigo-Alonso P1, Fernández-Mendívil C1, Cano-Peiró S1, Michalska P1, HHHW Schmidt3, León R1,2 and López MG1,2,*
1Instituto Teófilo Hernando (ITH). Madrid, Spain; 2Hospital Universitario de la Princesa. Madrid, Spain; 3Cardiovascular Research Institute, Maastricht, the Netherlands
Alzheimer´s disease (AD), characterized by a progressive and irreversible loss of cognitive function, is the most common form of dementia in the elderly. Besides β-amyloid aggregates and hyperphosphorylation of tau protein, which are the main histopathological hallmarks in AD, neuroinflammation and oxidative stress are gaining importance not only in the progression, but also in the initiation of the pathology. Furthermore, in the last few years, NOXs are very well situated to participate in perturbations related to cognitive function, and indeed, many reports have proposed that NOX may be involved in AD pathogenesis. Although the implication of NOX has been well established in β-amyloid related in vivo models, little or nothing is known about its relation with tau pathology, the main driver of neuron toxicity and brain atrophy in AD.
With all these premises, the aim of this work has been to elucidate the involvement of NOX-4 isoform in tau pathology. With this purpose, 4-months old C57/BL6 mice were injected with adeno-associated viral particles (AAV) containing the P301L human tau and GFP as a control (AAV-hTau/GFP). The intracerebroventricular injection of AAV-hTau generates inflammation, oxidative stress and autophagy impairment 7 days after its injection, without displaying any cognitive decline. Nevertheless, 28 days post injection, 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. Once the in vivo tau model was established, specific NOX-4 knocked-out mice were subjected to the toxicity exerted by AAV-hTau. Surprisingly, the deletion of this specific isoform avoids the increase in neuroinflammatory markers, as well as the alteration in the autophagic flux, halting the cognitive impairment. Therefore, we propose NOX-4 inhibition as a potential new therapeutic target to develop drugs for AD.
Funding: Thanks to the Spanish ministry grant “SAF2015-63935-R” to López MG. and to the continuous support of FTPGB.