Chemogenetic Modulation of Astrocytic Activity Rescues Hippocampus Associated Neurodegeneration in Alzheimer's Disease Mice Model 5xFAD.

Abstract

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by Aβ-amyloid accumulation and cognitive decline. Despite extensive research, effective treatments remain elusive. Astrocytes, the most abundant glial cells, play a crucial role in synaptic transmission, neuronal excitability, and plasticity. In AD, astrocytes become reactive, exhibiting aberrant calcium signaling and altered neurotransmitter release, making them promising targets for disease-modifying therapies. To address this, we explored designer receptors exclusively activated by designer drugs (DREADDs), specifically the hM3D(Gq) receptor, which selectively modulates intracellular Ca²⁺ levels in astrocytes upon activation by clozapine-N-oxide (CNO). Using daily CNO administration in 8-month-old 5xFAD mice, we observed a significant enhancement of impaired long-term potentiation formation, accompanied by cognitive improvements in the fear conditioning (FC) and Morris water maze (MWM) tests. Additionally, anxiety levels and social preference deficits in 5xFAD mice were fully restored following astrocytic activity modulation. Importantly, this approach reduced Aβ-amyloid plaque burden and demonstrated a trend toward mitigating astrocytic reactivity, further highlighting its therapeutic potential. Our findings suggest that targeting astrocytic activity via Gq-coupled receptors represents a novel and promising strategy for AD treatment, offering a noninvasive and effective approach to mitigating disease progression.