A second X chromosome contributes to resilience in a mouse model of Alzheimer’s disease

Emily J. Davis; Lauren Broestl; Samira Abdulai-Saiku; Kurtresha Worden; Luke W. Bonham; Elena Miñones-Moyano; Arturo J. Moreno; Dan Wang; Kevin Chang; Gina Williams; Bayardo I. Garay; Iryna Lobach; Nino Devidze; Daniel Kim; Cliff Anderson-Bergman; Gui-Qiu Yu; Charles C. White; Julie A. Harris; Bruce L. Miller; David A. Bennett; Arthur P. Arnold; Phil L. De Jager; Jorge J. Palop; Barbara Panning; Jennifer S. Yokoyama; Lennart Mucke; Dena B. Dubal

doi:10.1126/scitranslmed.aaz5677

Research ArticleAlzheimer’s Disease

A second X chromosome contributes to resilience in a mouse model of Alzheimer’s disease

View ORCID ProfileEmily J. Davis ¹,²,*,
View ORCID ProfileLauren Broestl¹,*,†,
View ORCID ProfileSamira Abdulai-Saiku¹,
View ORCID ProfileKurtresha Worden¹,‡,
View ORCID ProfileLuke W. Bonham¹,³,
View ORCID ProfileElena Miñones-Moyano¹,§,
View ORCID ProfileArturo J. Moreno¹,
Dan Wang¹,
View ORCID ProfileKevin Chang¹,
Gina Williams¹,⁴,
View ORCID ProfileBayardo I. Garay¹,||,
Iryna Lobach ⁵,
Nino Devidze⁶,¶,
Daniel Kim⁶,
View ORCID ProfileCliff Anderson-Bergman⁷,#,
Gui-Qiu Yu⁶,
View ORCID ProfileCharles C. White⁸,⁹,
View ORCID ProfileJulie A. Harris¹⁰,
View ORCID ProfileBruce L. Miller ¹,³,
View ORCID ProfileDavid A. Bennett ¹¹,
View ORCID ProfileArthur P. Arnold ¹²,
View ORCID ProfilePhil L. De Jager ⁹,
View ORCID ProfileJorge J. Palop¹,²,⁴,⁶,
Barbara Panning¹³,
Jennifer S. Yokoyama ¹,³,¹⁴,
View ORCID ProfileLennart Mucke ¹,²,⁴,⁶ and
View ORCID ProfileDena B. Dubal ¹,²,⁴,**

¹Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
²Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
³Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
⁴Neurosciences Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
⁵Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94158, USA.
⁶Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
⁷Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
⁸Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁹Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
¹⁰Allen Institute for Brain Science, Seattle, WA 98109, USA.
¹¹Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
¹²Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹³Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
¹⁴Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143, USA.

↵**Corresponding author. Email: dena.dubal{at}ucsf.edu

↵* These authors contributed equally to this work.
↵† Present address: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63130, USA.
↵‡ Present address: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
↵§ Present address: Synthego Corporation, Menlo Park, CA 94025, USA.
↵|| Present address: University of Minnesota Medical School, Minneapolis, MN 55455, USA.
↵¶ Present address: Sparks Therapeutics Inc., Philadelphia, PA 19104, USA.
↵# Present address: Lawrence Livermore National Laboratory, Livermore, CA 94550, USA.

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Science Translational Medicine 26 Aug 2020:
Vol. 12, Issue 558, eaaz5677
DOI: 10.1126/scitranslmed.aaz5677

Emily J. Davis

1Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

2Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.

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Lauren Broestl

1Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

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ORCID record for Lauren Broestl

Samira Abdulai-Saiku

1Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

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Kurtresha Worden

1Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

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Luke W. Bonham

1Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

3Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.

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Elena Miñones-Moyano

1Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

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Arturo J. Moreno

1Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

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Dan Wang

1Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

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Kevin Chang

1Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

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Gina Williams

1Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

4Neurosciences Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.

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Bayardo I. Garay

1Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

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Iryna Lobach

5Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94158, USA.

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Nino Devidze

6Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.

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Daniel Kim

6Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.

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Cliff Anderson-Bergman

7Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.

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Gui-Qiu Yu

6Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.

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Charles C. White

8Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

9Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.

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Julie A. Harris

10Allen Institute for Brain Science, Seattle, WA 98109, USA.

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Bruce L. Miller

1Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

3Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.

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David A. Bennett

11Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.

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Arthur P. Arnold

12Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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Phil L. De Jager

9Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.

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Jorge J. Palop

1Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

2Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.

4Neurosciences Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.

6Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.

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Barbara Panning

13Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.

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Jennifer S. Yokoyama

1Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

3Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.

14Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143, USA.

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Lennart Mucke

1Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

2Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.

4Neurosciences Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.

6Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.

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Dena B. Dubal

1Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

2Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.

4Neurosciences Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.

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For correspondence: dena.dubal@ucsf.edu

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The advantage of an extra X

Whether sex chromosomes contribute to sex difference in Alzheimer’s disease (AD) is unknown. In AD, men die earlier, whereas women live longer. During aging and preclinical AD, men show more cognitive deficits than do women. Davis et al. now report that the X chromosome may affect AD-related vulnerability in a mouse model of AD. Engineering mice to harbor a second X chromosome conferred resilience in male and female mice, in part through Kdm6a, an X chromosome gene that escapes inactivation. In humans, variation in the KDM6A gene was associated with higher expression in the brain and less cognitive decline. These results imply that having a second X chromosome could contribute to counteracting AD vulnerability.

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A second X chromosome contributes to resilience in a mouse model of Alzheimer’s disease

The advantage of an extra X

Science Translational Medicine

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