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Cell Rep. 2018 Feb 20;22(8):1974-1981. doi: 10.1016/j.celrep.2018.02.001.

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

Author information

1
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
2
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
3
Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
4
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, San Francisco, CA 94143, USA; The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: saul.villeda@ucsf.edu.

Abstract

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.

KEYWORDS:

Tet2; adult neurogenesis; aging; cognition; hippocampus; hydroxymethylation; rejuvenation

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