Astrocytic Activation Completely Corrects Memory Performance in an Alzheimer’s Disease Model

Authors:
  • TKTirzah Kreisel
    Tirzah Kreisel
  • YWYaara Weinstein
    Yaara Weinstein
  • MGMaya Groysman
    Maya Groysman
  • ADAdi Doron
    Adi Doron
  • RRRon Refaeli
    Ron Refaeli
  • MLMickey London
    Mickey London
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Abstract
Neural and glial dysfunction are thought to underlie memory impairments in Alzheimer’s disease (AD). Conversely, astrocytes are known to play a central role in the healthy brain, and their activation has been shown to enhance memory. To test whether activation of astrocytes can correct memory deficits associated with AD, we expressed hM3Dq in CA1 astrocytes of 7 months old 5XFAD AD model mice, enabling astrocytic chemogenetic Gq pathway activation, following exposure to CNO. We report that astrocytic activation results in complete memory correction, and even memory improvement of AD model mice beyond that of untreated WT levels. We went further to discover the mechanisms underlying this memory improvement in AD mice: First, using 2-photon imaging and electrophysiology, we observed increased neuronal activity (displayed as elevated cFos expression and amplified awake Ca 2+ events) as well as augmented in-vivo long term plasticity following astrocytic activation. Subsequently, we observed increased astrocytic endocytosis of Aβ plaques. Finally, we report that the beneficial effects of astrocytic activation remained stable for an entire year, and persisted beyond the window of astrocytic Gq activation. Our findings that astrocytes correct memory impairments in an AD model could have important clinical implications towards treating this disease.
Funding Information
  • European Research Council (101087731)

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