Tet2 Rescues Age-Related Regenerative Decline and Enhances Cognitive Function in the Adult Mouse Brain

Publication date: 20 February 2018
Source:Cell Reports, Volume 22, Issue 8
Author(s): Geraldine Gontier, Manasi Iyer, Jeremy M. Shea, Gregor Bieri, Elizabeth G. Wheatley, Miguel Ramalho-Santos, Saul A. Villeda
Restoring adult stem cell function provides an exciting approach for rejuvenating the aging brain. However, molecular mechanisms mediating neurogenic rejuvenation remain elusive. Here we report that the enzyme ten eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes the production of 5-hydroxymethylcytosine (5hmC), rescues age-related decline in adult neurogenesis and enhances cognition in mice. We detected a decrease in Tet2 expression and 5hmC levels in the aged hippocampus associated with adult neurogenesis. Mimicking an aged condition in young adults by abrogating Tet2 expression within the hippocampal neurogenic niche, or adult neural stem cells, decreased neurogenesis and impaired learning and memory. In a heterochronic parabiosis rejuvenation model, hippocampal Tet2 expression was restored. Overexpressing Tet2 in the hippocampal neurogenic niche of mature adults increased 5hmC associated with neurogenic processes, offset the precipitous age-related decline in neurogenesis, and enhanced learning and memory. Our data identify Tet2 as a key molecular mediator of neurogenic rejuvenation.

Graphical abstract

Teaser

Gontier et al. find a link between Tet2 and neurogenic rejuvenation. Age-related loss of hippocampal Tet2 and 5hmC associates with decreased neurogenesis. Mimicking age-related loss of Tet2 in the young mouse hippocampus decreases neurogenesis and impairs cognition. Restoring Tet2 in the mature hippocampus rejuvenates regenerative capacity and enhances cognition.


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