Expressing a specific isoform of the klotho protein boosts memory in middle-aged and older mice, suggests a study in the October 31 Molecular Psychiatry. Scientists led by Miguel Chillón, Universitat Autònoma, Barcelona, Spain, reported that memory in aging wild-type mice held up better when they expressed a secreted isoform of the protein in the brain for six months. “We believe the results indicate secreted klotho has great therapeutic potential,” wrote Chillón to Alzforum. “Future research should explore its suitability to treat dementia and neurodegenerative disorders, such as Alzheimer's.”
- Scientists expressed a brain-specific form of the klotho protein in mice.
- It countered age-related decline in working and long-term memory.
- Results could have therapeutic implications for dementia.
Most studies to date have examined the full-length version of the transmembrane protein, or a version that is cleaved and released from the membrane. However, Chillón and colleagues previously found that alternative splicing leads to a stable, truncated isoform known as secreted klotho, or s-KL. This protein expresses almost exclusively in the brain (Massó et al., 2015). Given that, Chillón’s group wondered if s-KL might play a neuroprotective role in cognition.
To find out, first author Anna Massó and colleagues overexpressed s-KL in the brains of wild-type C57BL/6J mice. To avoid any developmental effects, they waited until the animals were either six or 12 months old. Then they injected their brains with an AAVrh10 virus encoding the s-KL protein. This one-time treatment caused neurons to produce s-KL for the rest of the animals’ lives. Six-month-old animals got the shot directly into the hippocampus because the researchers wanted to see how effective the protein was in an area that produces a lot of endogenous klotho and that plays a crucial role in memory. Twelve-month-old animals received injections in the ventricles of the brain. In six-month-old animals, the researchers also tested the effect of decreasing expression of endogenous s-KL by using an AAV virus carrying small-hairpin RNA (shRNA) specific for the protein. Massó and colleagues tested learning and memory in all treated mice six months after their respective injections.
Now 12 and 18 months old, the s-KL recipients performed better on tests of learning and memory than untreated mice. In the T-maze, which examines working memory, treated mice more quickly explored all three arms and backtracked less often to an arm they had already visited. Mice also better remembered the location of a hidden platform 24 hours after training on the Morris water maze, suggesting they had better long-term memory. The animals treated at six months also exhibited more robust short-term memory than untreated mice, with better performance two hours after the last training trial in the water maze. Conversely, the animals treated with the shRNA navigated the T and Morris water mazes poorly relative to untreated controls.
Results imply that s-KL is important for cognitive functions, wrote the authors, though the function of the protein is still unknown. That one injection protected against decline in learning and memory in aged animals hints that a related therapy could one day help treat or prevent dementia, they wrote.
“It is exciting to see more and more evidence for a role of klotho in improving cognitive functions in aging,” wrote Dena Dubal, University of California, San Francisco, to Alzforum. She recently found that peripheral treatment with the cleaved version of klotho improved learning and memory in young and aging mice, and countered deficits in a mouse model that overexpresses α-synuclein (Aug 2017 news). “In a terrific new twist, Massó and colleagues show that central delivery of another form of klotho improved cognition. Whether the mechanisms of action of peripheral or central klotho treatment converge remains to be determined,” she wrote.—Gwyneth Dickey Zakaib
- Massó A, Sánchez A, Gimenez-Llort L, Lizcano JM, Cañete M, García B, Torres-Lista V, Puig M, Bosch A, Chillon M. Secreted and Transmembrane αKlotho Isoforms Have Different Spatio-Temporal Profiles in the Brain during Aging and Alzheimer's Disease Progression. PLoS One. 2015;10(11):e0143623. Epub 2015 Nov 24 PubMed.
- Li Q, Vo HT, Wang J, Fox-Quick S, Dobrunz LE, King GD. Klotho regulates CA1 hippocampal synaptic plasticity. Neuroscience. 2017 Apr 7;347:123-133. Epub 2017 Feb 12 PubMed.
- Dubal DB, Zhu L, Sanchez PE, Worden K, Broestl L, Johnson E, Ho K, Yu GQ, Kim D, Betourne A, Kuro-O M, Masliah E, Abraham CR, Mucke L. Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice. J Neurosci. 2015 Feb 11;35(6):2358-71. PubMed.
- Massó A, Sánchez A, Bosch A, Giménez-Llort L, Chillón M. Secreted αKlotho isoform protects against age-dependent memory deficits. Mol Psychiatry. 2017 Oct 31; PubMed.