Life Extension Factor Klotho Enhances Cognition

被引：247

作者：

Dubal, Dena B. ^{[1
,2
]}

Yokoyama, Jennifer S. ^{[2
]}

Zhu, Lei ^{[1
,2
]}

Broestl, Lauren ^{[2
]}

Worden, Kurtresha ^{[1
,2
]}

Wang, Dan ^{[2
]}

Sturm, Virginia E. ^{[2
]}

Kim, Daniel ^{[1
]}

Klein, Eric ^{[3
]}

Yu, Gui-Qiu ^{[1
]}

Ho, Kaitlyn ^{[1
]}

Eilertson, Kirsten E. ^{[4
]}

Yu, Lei ^{[5
]}

Kuro-o, Makoto ^{[6
,7
]}

De Jager, Philip L. ^{[8
,9
,10
,11
]}

Coppola, Giovanni ^{[3
]}

Small, Gary W. ^{[3
]}

Bennett, David A. ^{[5
]}

Kramer, Joel H. ^{[2
]}

Abraham, Carmela R. ^{[12
]}

Miller, Bruce L. ^{[2
]}

Mucke, Lennart ^{[1
,2
]}

机构：

[1] Gladstone Inst Neurol Dis, San Francisco, CA 94158 USA

[2] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA

[3] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA

[4] Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA

[5] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA

[6] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA

[7] Jichi Med Univ, Ctr Mol Med, Shimotsuke, Tochigi 3290498, Japan

[8] Brigham & Womens Hosp, Inst Neurosci, Program Translat NeuroPsychiat Genom, Dept Neurol, Boston, MA 02115 USA

[9] Brigham & Womens Hosp, Inst Neurosci, Program Translat NeuroPsychiat Genom, Dept Psychiat, Boston, MA 02115 USA

[10] Harvard Univ, Sch Med, Boston, MA 02115 USA

[11] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[12] Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA

来源：

CELL REPORTS | 2014年 / 7卷 / 04期

关键词：

LONG-TERM POTENTIATION; NR2B-CONTAINING NMDA RECEPTORS; ALZHEIMERS-DISEASE; GENETIC ENHANCEMENT; FUNCTIONAL VARIANT; APOLIPOPROTEIN-E; TRANSGENIC MICE; MEMORY; ASSOCIATION; ANTAGONIST;

D O I：

10.1016/j.celrep.2014.03.076

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a lifespan-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers. Because this allele increased klotho levels in serum, we analyzed transgenic mice with systemic overexpression of klotho. They performed better than controls in multiple tests of learning and memory. Elevating klotho in mice also enhanced long-term potentiation, a form of synaptic plasticity, and enriched synaptic GluN2B, an N-methyl-D-aspartate receptor (NMDAR) subunit with key functions in learning and memory. Blockade of GluN2B abolished klotho-mediated effects. Surprisingly, klotho effects were evident also in young mice and did not correlate with age in humans, suggesting independence from the aging process. Augmenting klotho or its effects may enhance cognition and counteract cognitive deficits at different life stages.

引用

页码：1065 / 1076

页数：12

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