Sunday , February 21 , 2010 3 a Symposium 1 : Amyloids in Human Disease

14-Symp Dysregulation of Intracellular Calcium in Alzheimer’s Disease Brian J. Bacskai, Kishore V. Kuchibhotla, Carli Lattarulo, Bradley T. Hyman. Massachusetts Gen Hosp, Charlestown, MA, USA. Alzheimer’s disease is characterized by the deposition of senile plaques in the brain resulting in focal neurotoxicity that ultimately leads to neural network disruption. Intracellular calcium is a tightly regulated second messenger whose activation leads to numerous downstream events, including cell death. It has been suggested that dysregulation of calcium homeostasis plays a role in Alzheimer’s disease, however this has not been demonstrated directly. We combined in vivo multiphoton cell-resolved calcium imaging to quantitatively image resting and dynamic calcium signaling in both neurons and astrocytes in the brains of mouse models of AD. We found that resting calcium was elevated in a subset of neurons and throughout the astrocytic network in mice with cortical plaques. This increase in calcium levels in neurons but not astrocytes, depended on the proximity to individual senile plaques. The neuronal calcium overload was not the result of presenilin mutations, and led to the loss of spinodendritic compartmentalization, important for synaptic coordination. In astrocytes, we observed increased spontaneous calcium transients that were not dependent on neuronal activity. Astrocytes were functionally coupled across long distances in APP transgenic but not wildtype mice with evidence of in vivo intercellular calcium waves originating near plaques and spreading to astrocytes nearly 200 microns away. These data reveal disruptions in calcium homeostasis in both neurons and astrocytes in mouse models of AD with differing spatial ramifications. Together, the results demonstrate that the aberrant intracellular calcium levels in the brain provide insight into the pathophysiology of AD and that specific manipulation of calcium levels may lead to new drug targets.