Chronokines are proteins that play a role in the aging process and pathologies associated to it, primarily by modulating the metabolism, oxidative stress, and inflammation. Different chronokines, such as the anti-aging factor Klotho, have been shown to present beneficial effects on aging associated diseases such as Alzheimer’s disease.

 

aKlotho presents various isoforms, a transmembrane protein, which can be processed into a soluble form, and a secreted isoform (sKL) generated through alternative splicing. Beneficial effects on cognition have been attributed to Klotho isoforms.

 

Given the effects of Klotho on neurodegenerative diseases, we studied a therapeutical approach based on a novel chimeric chronokine derived from Klotho. Six-month-old APP/Tau mice were intraperitoneally injected with a 9.P31 AAV vector capable of crossing the blood-brain barrier, and different behavioral tests were carried out three months later, including Novel Object Recognition, T-maze, and Morris Water Maze. Of note, treated mice showed a cognitive improvement compared to non-treated littermates, while no visible differences were seen in anxiety-related behaviors.

 

Furthermore, while no toxic effect of the treatment was observed in blood, improvements were observed in immunofluorescence and RNAseq analyses.

 

In conclusion, a novel chronokine administration has proven to be a promising therapeutical approach for protecting against cognitive decline associated with Alzheimer’s disease in mice. Further research in other animal models, including non-human primates, is necessary to test if this strategy could be used for a future application in human subjects.