Abstract
The physiological function of the neurovascular unit is critically dependent upon the complex structure and functions of astrocytes for optimal preservation of cerebral homeostasis. While it has been shown that astrocytes exhibit aberrant changes in both structure and function in transgenic murine models of Alzheimer’s disease (AD), it is not fully understood how this altered phenotype contributes to the pathogenesis of AD or whether this alteration predicts a therapeutic target in AD. The mechanisms underlying the spatiotemporal relationship between astrocytes, neurons and the vasculature in their orchestrated regulation of local cerebral flow in active brain regions has not been fully elucidated in brain physiology and in AD. As there is an incredible urgency to identify therapeutic targets that are well-tolerated and efficacious in protecting the brain against the pathological impact of AD, here we use the current body of literature to evaluate the hypothesis that pathological changes in astrocytes are central to the pathogenesis of AD. We also examine the current tools available to assess astrocytic calcium signaling in the living murine brain as it has an important role in the complex interaction between astrocytes, neurons and the vasculature. Furthermore, we discuss the altered function of astrocytes in their interaction with neurons in the preservation of glutamate homeostasis and additionally address the role of astrocytes at the vascular interface and their contribution to functional hyperemia within the living murine brain in health and in AD.
Highlights
Recent global estimates indicate that over 46 million individuals are living with dementia (Prince, 2017) and current clinical therapies are unable to slow progressive neurodegeneration
Reactive astrocytes undergo a complex cascade of morphological alterations that include hypertrophy and the upregulation of cytoskeleton proteins such as glial fibrillary acidic protein (GFAP) and vimentin, which may interfere with the multitude of complex physiological homeostatic functions conducted by astrocytes and contribute to the evolution of Alzheimer’s disease (AD)
Position emission tomography (PET) imaging studies using the tracer 11C-deuterium-L-deprenyl, directed towards the monoamine oxidase B enzyme, reported that reactive astrocytes are present in patients at early stages of AD, those patients with Mild Cognitive Impairment (MCI) (Carter et al, 2012) and that reactive astrocytes precede amyloid plaques in a mouse model of AD (Rodriguez-Vieitez et al, 2015)
Summary
Recent global estimates indicate that over 46 million individuals are living with dementia (Prince, 2017) and current clinical therapies are unable to slow progressive neurodegeneration. Astrocytic Role in Alzheimer’s Disease disease severity and amyloid plaque burden reached a plateau early in the pathogenesis of AD (Serrano-Pozo et al, 2011). Position emission tomography (PET) imaging studies using the tracer 11C-deuterium-L-deprenyl, directed towards the monoamine oxidase B enzyme, reported that reactive astrocytes are present in patients at early stages of AD, those patients with Mild Cognitive Impairment (MCI) (Carter et al, 2012) and that reactive astrocytes precede amyloid plaques in a mouse model of AD (Rodriguez-Vieitez et al, 2015)
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