Monday, March 31, 2025
3/31/2025
Astrocytes as governing pathological drivers of neurovascular dysfunction in AD - Astrocytes as governing pathological drivers of neurovascular dysfunction in AD Abstract: Alzheimer’s Disease (AD) is a progressive and irreversible neurodegenerative disease, characterized by cognitive decline. The pathogenesis of AD is complex, and the etiology has yet to be fully elucidated. The pathological manifestations of AD involve amyloid (Abeta) plaques and neurofibrillary tangles (NFTs), as well as a significant synaptic loss and neuronal degeneration, and a neuroinflammatory process accompanied by microglial and astrocytic activation. Specifically, the role of astrocytes in AD is very limited, although their contribution is likely crucial in the initiation and progression of AD. Astrocytes undertake numerous fundamental functions for the general homeostasis of the central nervous system, maintaining normal brain activities, and are key players in aging and dementia. Astrocytes are vital for maintaining the health of the neurovascular unit such as (but not limited to): contributing to synaptic transmission, blood flow dynamics, neurovascular coupling, glutamate homeostasis, potassium homeostasis, osmotic regulation, removal of interstitial waste products from the parenchyma, contributing to blood-brain barrier (BBB) function, sleep health and wakefulness. Astrocytes play an important role in functional hyperemia, in which local increases in blood flow meet the metabolic demands of increased neuronal activity. These findings highlight astrocytes as a central player within the neurovascular unit. Astrocytes demonstrate functional activity through calcium signaling, however, the role of astrocytic calcium signaling pathophysiology in neurovascular unit dysfunction remains poorly understood. We will test our governing hypothesis that astrocytic calcium signaling pathophysiology is a major governing pathological driver of neurovascular unit dysfunction in AD and an exciting and novel disease modifying therapeutic target. We have powerful in vivo tools and expertise to thoroughly test this hypothesis in vivo with multiphoton microscopy. We will image calcium concentrations and dynamics using genetically encoded calcium reporters targeted to astrocytes or neurons in all of the cellular compartments within single astrocytes, along with amyloid deposits, the vasculature, and neuronal calcium signaling to identify the mechanism of the astrocyte pathophysiology observed in mouse models of AD. We will interrogate the system through observations of plaque proximity, test the direct role of soluble Abeta oligomers, and use a functional hyperemia approach based on a visual stimulation paradigm to evaluate the deterioration of the function of the complete neurovascular unit. These experiments in total will determine which components of the neurovascular unit are compromised and when over the lifetime of the mice. Ultimately, this will guide decisions for the development of novel therapeutic approaches in AD.
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