Journal Article Epublish
PubMed: 40777052 DOI: 10.1016/j.isci.2025.113120
Impaired neuromodulator crosstalk delays arousal-dependent astroglia Ca 2+ activation in mouse models of Alzheimer's disease.
iScience 28(8):113120
Authors: Eunice Y Heo, Angelica Salinas-Birt, Liang Ye, Sanaz Sajadi, Mithun K Sarker, Yongjie Yang, Martin Paukert
Affiliations
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
- Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
- Department of Neuroscience, Tufts University, Boston, MA 02111, USA.
Abstract
Cortical astrocyte Ca 2+ activation is associated with control of neuronal network activity and is altered in mouse models of Alzheimer's disease (AD). Applying enforced running, a well-controlled behavioral paradigm triggering arousal-mediated widespread Ca 2+ activation in astroglia throughout the brain, to two mouse models of AD (APPswe/PSEN1dE9 and App NL-F KI), we consistently observed delayed and less coordinated astrocyte Ca 2+ elevations. Combining pharmacological and genetic manipulations, we found that direct noradrenergic signaling to astrocytes was facilitated by cholinergic signaling, but this neuromodulator crosstalk was impaired in App NL-F mice. Pharmacological facilitation of norepinephrine release rescued delayed and less coordinated astrocyte Ca 2+ activation in both mouse models and suggests that astrocytes preserve a functional reserve that can be recruited even during late-stage disease. Our findings demonstrate that impaired cholinergic facilitation of noradrenergic signaling in mouse models of AD contributes to altered astroglia Ca 2+ activation and may represent a mechanism involved in cognitive decline.
MeSH
Astrocytes, Alzheimer Disease, Arousal, Cholinergic Agents