Brian J. Bacskai, United States of America
MassGeneral Institute for Neurodegenerative Disease NeurologyAuthor Of 1 Presentation
HYPERACTIVE SPONTANEOUS INTRA- AND INTER-CELLULAR CALCIUM ACTIVITY WITHIN CORTICAL ASTROCYTES OF AWAKE APP/PS1 TRANSGENIC MICE
Abstract
Aims
Astrocytes generate spontaneous calcium events whilst performing homeostatic functions essential for optimal cerebral function. We hypothesized that spontaneous astrocytic calcium activity is hyperactive throughout cellular compartments within the awake APP/PS1 mouse brain.
Methods
We expressed the ratiometric calcium indicator, yellow cameleon, specifically within cortical astrocytes of 12-17 months old APP/PS1 transgenic mice (n=10) and non-transgenic littermates (n=9). Using multiphoton microscopy, we qualitatively and quantitatively measured spontaneous astrocytic calcium activity, through a chronic craniotomy over the somatosensory cortex, of awake habituated mice. Time-lapse imaging was analyzed using custom-written MATLAB scripts.
Results
‘Silent’ astrocytes, with a stable YFP/CFP ratio, accounted for 17/60 (28%) astrocytes in wild-type mice and 22/69 (32%) astrocytes in APP/PS1 mice. There were 12 spontaneous ‘localized’ events within the astrocytic primary processes of wild-type mice compared to 25 ‘localized’ events within the astrocytic primary processes of APP/PS1 mice. Wild-type astrocytic endfeet exhibited 27 ‘localized’ events compared to 11 ‘localized’ events within the astrocytic endfeet of APP/PS1 mice. ‘Multicompartmental’ events occurred with greater amplitude in the somas of APP/PS1 mice when compared to wild-type mice (p=0.009). Heterogeneous ‘multicellular’ events occurred with greater amplitude in the somas (p=0.01) and primary processes (p=0.0029) of APP/PS1 mice when compared to wild-type mice.
Conclusions
Here we reveal the heterogeneous complexity, compartmentalization and pathological hyperactivity of spontaneous intra- and inter-cellular calcium activity, most likely coupled to aberrant astrocytic function, within the astrocytic network and neurovascular unit of the awake APP/PS1 mouse brain. These data suggest that therapeutics targeting astrocyte activity represent an alternative target for treating Alzheimer’s disease.