In Vivo Two Photon Imaging of Astrocytic Structure and Function in Alzheimer’s Disease

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.

Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice

“…The Ca 2+ hypothesis in LOAD contends that aberrant Ca 2+ responses in neurons associated with Aβ, Tau, and the glutamatergic system underlie cognitive impairment [100]. In addition, Ca 2+ signaling is profoundly dysregulated in astrocytes in animal models of AD [39,101], mainly due to aberrant activation of purinergic receptors [56]. Our results support the notion that APOE4 may exacerbate the dysregulation of Ca 2+ signaling in male astrocytes in LOAD owing to lysosomal dysfunction caused by lipid dyshomeostasis.…”

Targeting microglia L‐type voltage‐dependent calcium channels for the treatment of central nervous system disorders

“…In rodent models of AD, intracellular Ca 2+ dysregulation is observed in several cell types near amyloid plaque deposits, including neurons (Arbel-Ornath et al, 2017;Kuchibhotla et al, 2008), astrocytes (Kuchibhotla, Lattarulo, Hyman, & Bacskai, 2009), and microglia (Brawek et al, 2014). While the consequences of altered intracellular Ca 2+ dynamics near plaques in AD are not fully understood, increased intracellular Ca 2+ can interfere with normal synaptic plasticity and contribute to excitotoxicity in neurons (Paula-Lima et al, 2011), is involved with formation of pathological lesions (Stutzmann, 2007), may dysregulate astrocyte-mediated hemodynamics (Kelly, Hudry, Hou, & Bacskai, 2018), and perturb microglia stimuli responsiveness (Brawek et al, 2014).…”

How Long Are Reperfusion Therapies Beneficial for Patients after Stroke Onset? Lessons from Lethal Ischemia Following Early Reperfusion in a Mouse Model of Stroke

“…Presently, the application of reperfusion therapies is determined by neuroimaging like computed tomography and magnetic resonance imaging. In animal brains, real-time in vivo imaging by two-photon microscopy enables image acquisition of dynamic cell-cell interactions [ 4 , 5 ]. In human brains, although neuroimaging evaluating ischemic lesions and/or the neurovascular unit (NVU) has advanced considerably [ 6 , 7 , 8 , 9 , 10 , 11 ], it cannot fully assess metabolic processes within ischemic areas [ 12 ].…”