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Optogenetic Targeting of Astrocytes Restores Sleep-Dependent Brain Rhythm Function and Slows Alzheimer's Disease

26 Pages Posted: 8 Apr 2022 Publication Status: Review Complete

See all articles by Yee Fun Lee

Yee Fun Lee

Boston University

Alyssa N. Russ

affiliation not provided to SSRN

Qiuchen Zhao

affiliation not provided to SSRN

Megi Maci

Massachusetts General Hospital; Massachusetts General Hospital – MassGeneral Institute for Neurodegenerative Disease (MIND)

Morgan R. Miller

affiliation not provided to SSRN

Steven S. Hou

affiliation not provided to SSRN

Moustafa Algamal

Harvard University - Massachusetts General Hospital

Alfonso Araque

University of Minnesota

Elena Galea

affiliation not provided to SSRN

Brian J. Bacskai

affiliation not provided to SSRN

Ksenia Kastanenka

Massachusetts General Hospital and Harvard Medical School - Department of Neurology

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Abstract

Patients with Alzheimer’s disease (AD) exhibit sleep disturbances, specifically deficits in deep non-rapid eye movement (NREM) sleep. Disruption of NREM slow waves occurs early in the disease progression and is recapitulated in transgenic mouse models of beta-amyloidosis. However, the mechanisms underlying slow-wave disruptions remain unknown. Also, it is not clear if these sleep disturbances are a cause or effect of AD. Because astrocytes contribute to slow-wave activity, we used multiphoton microscopy and optogenetics to investigate whether they contribute to slow-wave disruptions in APP mice. The power but not the frequency of astrocytic calcium transients was reduced. Optogenetic activation of astrocytes at the endogenous frequency of slow waves restored slow-wave power, reduced amyloid deposition, prevented neuronal calcium elevations, and improved memory performance. Our findings revealed malfunction of the astrocytic network driving slow-wave disruptions. Thus, targeting astrocytes to restore circuit activity underlying sleep and memory disruptions in AD could ameliorate disease progression.

Keywords: optogenetics, astrocytes, sleep, slow oscillations, Alzheimer's Disease, Multiphoton imaging, neuroinflammation, memory consolidation, calcium

Suggested Citation

Lee, Yee Fun and Russ, Alyssa N. and Zhao, Qiuchen and Maci, Megi and Miller, Morgan R. and Hou, Steven S. and Algamal, Moustafa and Araque, Alfonso and Galea, Elena and Bacskai, Brian J. and Kastanenka, Ksenia, Optogenetic Targeting of Astrocytes Restores Sleep-Dependent Brain Rhythm Function and Slows Alzheimer's Disease. Available at SSRN: https://ssrn.com/abstract=4079101 or http://dx.doi.org/10.2139/ssrn.4079101
This version of the paper has not been formally peer reviewed.

Yee Fun Lee

Boston University ( email )

595 Commonwealth Avenue
Boston, MA 02215
United States

Alyssa N. Russ

affiliation not provided to SSRN ( email )

No Address Available

Qiuchen Zhao

affiliation not provided to SSRN ( email )

No Address Available

Megi Maci

Massachusetts General Hospital ( email )

Boston, MA
United States

Massachusetts General Hospital – MassGeneral Institute for Neurodegenerative Disease (MIND) ( email )

Charlestown Navy Yard, 16th Street
Building 114
Charlestown, MA 02129
United States

Morgan R. Miller

affiliation not provided to SSRN ( email )

No Address Available

Steven S. Hou

affiliation not provided to SSRN ( email )

No Address Available

Moustafa Algamal

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Alfonso Araque

University of Minnesota ( email )

10 University Avenue
Duluth, MN 55810

Elena Galea

affiliation not provided to SSRN ( email )

No Address Available

Brian J. Bacskai

affiliation not provided to SSRN ( email )

No Address Available

Ksenia Kastanenka (Contact Author)

Massachusetts General Hospital and Harvard Medical School - Department of Neurology ( email )

Charlestown, MA 02129
United States

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