Astrocytes are the most abundant cells in the central nervous system, however their role in health and disease remains a mystery. Astrocytes are very heterogeneous in structure and molecular profile. A single astrocyte creates a distinct non-overlapping territory that encompasses thousands of synapses. Their extensive branches and fine processes allow direct communication over long distances, as well as indirect communication through secretion of chemokines and cytokines. Astrocytes are also a significant component of the neurovascular unit as their endfeet processes terminate directly onto cerebral vessels, regulating cerebral blood flow according to metabolic demand. While in vitro models, including primary astrocytes and acute brain slices, have provided great insight into the physiology of astrocytes in health and disease scenarios, it is clear these preparations devoid of the complexity of the role of astrocytes in vivo. Thus, efforts to study astrocyte physiology should be directed as much as possible to the most physiologically relevant system: the intact living brain. We and others have demonstrated through in vivo imaging of intracellular calcium that astrocytes are dynamic players in the brain, and that the progression of Alzheimer's disease pathology alters their morphology and signaling characteristics. More specifically, we determined that in the presence of senile plaques, astrocytes in the brain have elevated intracellular calcium, exhibit hyperactive signaling, and can initiate spontaneous calcium waves. This allows astrocytes to respond to focal pathological insults with both focal and long range responses. These observations demonstrated that astrocytes respond to amyloid deposition with a change in function, but left several fundamental questions unanswered. Here, we wish to extend our previous observations and determine what the contribution of the altered calcium signaling is to the degenerative process that occurs in AD. The use of genetically encoded indicators, specifically expressed in astrocytes, along with in-vivo imaging will allow us to explore the effect of amyloid on astrocyte structure and function at the synapse and the neurovascular unit. We will also determine if the alterations depend on senile plaque deposition, or soluble oligomeric A? and whether the alterations are beneficial or detrimental to brain function. We propose experiments where astrocyte specific increases or decreases in calcium signaling will be evaluated in healthy and diseased brains. Finally, we will ask how clinically relevant manipulation of the amyloid cascade will affect calcium signaling in astrocytes and the degenerative process. These experiments will shed light on the role of astrocytes in the healthy and diseased brain, and will lead to new targets for therapeutic manipulation in Alzheimer's disease.

Public Health Relevance

Astrocytes are the most abundant cells in the central nervous system, however their role in health and disease remains a mystery. Astrocytes play many roles in maintaining a healthy nervous system, including control of synaptic function and oxygen supply through the blood. These cells communicate with the neuronal population as well as with neighboring astrocytes via calcium signals and secretion of small molecules (gliotransmission). We have recently described abnormal calcium signaling in astrocytes of transgenic mice used to study Alzheimer's disease. Here, we wish to further extend our observations and ask are these aberrant signals are protective or deleterious in nature, how this phenotype affect normal astrocytes function regarding regulation of synaptic function and vascular function and finally we will test therapeutic strategies , currently tested in the clinic, and evaluate their ability to reverse the abnormal calcium signaling in astrocytes. The finding of this study will increase our understanding of astrocytes function in health and disease and will reveal novel therapeutic targets that may delay disease progression.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG054598-01A1
Application #
9329865
Study Section
Neuroscience and Ophthalmic Imaging Technologies Study Section (NOIT)
Program Officer
Wise, Bradley C
Project Start
2017-03-01
Project End
2022-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
1
Fiscal Year
2017
Total Cost
$376,533
Indirect Cost
$143,605
Name
Massachusetts General Hospital
Department
Type
Independent Hospitals
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114