Astrocyte calcium dysregulation and cerebrovascular impairments in the 5XFAD mouse model of familial Alzheimer’s disease
Blaine E. Weiss, John C Gant, Pradoldej Sompol, Olivier Thibault, Susan D. Kraner, Christopher M. Norris- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Amyloid deposits (Aβ) in the brain are a primary diagnostic marker of Alzheimer’s disease, and are associated with the degeneration of synapses and cognitive decline. However, recent advances in cell specific approaches have revealed that glial processes may also contribute to the progression of disease pathology. Astrocytes are a glial cell in the brain responsible for a plethora of essential functions in the brain, such as the removal of synaptic glutamate, and control over cerebrovascular function. Astrocyte Ca2+ signaling is closely coupled to these functions. These pathways are dysregulated with disease onset, and contribute to astrocyte reactivity. Our group showed previously in a diet model of VCID, that changes in astrocyte calcium signaling and network synchronicity were associated with deficits in cerebrovascular function. Here we examined the spatial and temporal relationship of astrocyte Ca2+ signals to neurovascular coupling in 5XFAD mice to determine the relationship between reactive astrocytes and cerebrovascular function.
Method
5XFAD and littermate controls aged to 6 months were injected with AAV2/5‐Gfa104‐jGCaMP8f into barrel cortex before cranial window installation. At 7 months, mice were briefly anaesthetized before retroorbital injection of 500kb rhodamine dextran. Mice were then imaged awake under a two‐photon microscope for functional hyperemia measures in response to timed air puff whisker stimulation. Spontaneous and evoked Ca2+ transients were measured by ∆F/F calculation of Ca2+ peaks extracted by custom MATLAB algorithms. Analysis of astrocyte endfoot Ca2+ was measured along vessels stimulated for neurovascular coupling to relate vasoactivity to Ca2+ signaling kinetics and intensity.
Result
5XFAD mice showed a significant reduction is astrocyte Ca2+ rise time kinetics compared to wild type controls, as well as parameters of functional hyperemia. Timing of neurovascular coupling in response to stimulation and the latency of astrocyte calcium kinetics was characterized for the 5XFAD model and shown to differ between soma and endfoot processes.
Conclusion
Amyloid induced pathology induces changes in astrocyte Ca2+ signaling. Dysregulation of astrocyte signaling may have a mechanistic role in the kinetics of neurovascular coupling and/or cerebrovascular dysfunction with disease progression. However, further analysis of astrocyte endfoot coverage and manipulation of astrocyte signaling during functional hyperemia is needed to further clarify mechanism.