Compartment-specific analysis reveals disrupted astrocytic calcium transients in Alzheimer’s mice

TL;DR

This study finds that Alzheimer’s disease disrupts calcium signaling in specific parts of astrocytes in mice, which could affect brain function.

Contribution

The study provides the first systematic analysis of calcium dynamics in specific astrocytic compartments in Alzheimer’s disease.

Findings

Astrocytic somas in Alzheimer’s mice showed increased activity duration and peak amplitude.

Processes and microdomains in Alzheimer’s mice had reduced calcium activity despite higher event rates.

Endfeet showed reductions in all calcium parameters, and enhanced astrocyte synchrony was observed in Alzheimer’s mice.

Abstract

Alzheimer’s disease (AD) is characterized by presence of extracellular amyloid plaques, intracellular tau tangles, and extensive neuronal cell death. In addition to neurons, astrocytes modulate neuronal network activity through tripartite synapses and are increasingly recognized for their involvement in AD pathology. Astrocytic calcium signaling has been implicated in AD pathological processes, including disrupted synaptic transmission, dysregulated glutamate homeostasis, and impaired vascular function via astrocytic endfeet. However, a systematic analysis of calcium dynamics within specific astrocytic compartments has been lacking. Using in vivo multiphoton imaging of Yellow Cameleon 3.6, a genetically encoded calcium indicator targeted to astrocytes in APP/PS1 mice, we analyzed spontaneous calcium transients in cortical astrocytes at 4–6 months of age. We quantified event rate, activity duration, area under the curve (AUC), and peak amplitude across four compartments: soma, processes, microdomains, and endfeet. In APP/PS1 mice, somas exhibited increased activity duration and peak amplitude, while processes and microdomains showed reduced duration, AUC, and amplitude despite higher event rates. Endfeet showed reductions in all parameters. Correlation analysis revealed enhanced astrocyte synchrony in APP/PS1 mice, with distance-dependent correlation decay observed only in nontransgenic controls. Our findings highlight compartment-specific disruptions of astrocytic calcium activity caused by amyloidosis.

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