Impaired Hippocampal Neurovascular Coupling in a Mouse Model of Alzheimer's Disease.

Lin Li,Hélène Girouard,Xin-Kang Tong,Mohammadamin Hosseini Kahnouei,Diane Vallerand,Edith Hamel

doi:10.3389/fphys.2021.715446

Abstract

Alzheimer’s disease (AD), the most common form of dementia, is characterized by neuronal degeneration and cerebrovascular dysfunction. Increasing evidence indicates that cerebrovascular dysfunction may be a key or an aggravating pathogenic factor in AD. This emphasizes the importance to investigate the tight coupling between neuronal activity and cerebral blood flow (CBF) termed neurovascular coupling (NVC). NVC depends on all cell types of the neurovascular unit within which astrocytes are important players in the progression of AD. Hence, the objective of this study was to characterize the hippocampal NVC in a mouse model of AD. Hippocampal NVC was studied in 6-month-old amyloid-beta precursor protein (APP) transgenic mice and their corresponding wild-type littermates using in vivo laser Doppler flowmetry to measure CBF in area CA1 of the hippocampus in response to Schaffer collaterals stimulation. Ex vivo two-photon microscopy experiments were performed to determine astrocytic Ca2+ and vascular responses to electrical field stimulation (EFS) or caged Ca2+ photolysis in hippocampal slices. Neuronal synaptic transmission, astrocytic endfeet Ca2+ in correlation with reactive oxygen species (ROS), and vascular reactivity in the presence or absence of Tempol, a mimetic of superoxide dismutase, were further investigated using electrophysiological, caged Ca2+ photolysis or pharmacological approaches. Whisker stimulation evoked-CBF increases and ex vivo vascular responses to EFS were impaired in APP mice compared with their age-matched controls. APP mice were also characterized by decreased basal synaptic transmission, a shorter astrocytic Ca2+ increase, and altered vascular response to elevated perivascular K+. However, long-term potentiation, astrocytic Ca2+ amplitude in response to EFS, together with vascular responses to nitric oxide remained unchanged. Importantly, we found a significantly increased Ca2+ uncaging-induced ROS production in APP mice. Tempol prevented the vascular response impairment while normalizing astrocytic Ca2+ in APP mice. These findings suggest that NVC is altered at many levels in APP mice, at least in part through oxidative stress. This points out that therapies against AD should include an antioxidative component to protect the neurovascular unit.

Highlights

Alzheimer’s disease (AD), the most common form of dementia in the elderly, is characterized by progressive memory decline and deficits
In APP mice compared to WT controls, (i) the in vivo CBF increase in response to Schaffer collaterals stimulation is reduced, and (ii) the ex vivo vasodilation in response to neuronal stimulation or astrocytic Ca2+ elevation is diminished
Scavenging Reactive oxygen species (ROS) with Tempol in APP mice normalized the vascular responses to neuronal stimulation and astrocytic Ca2+ elevations

Summary

Introduction

Alzheimer’s disease (AD), the most common form of dementia in the elderly, is characterized by progressive memory decline and deficits. The disease is defined by pathological features such as amyloid β accumulation, hyperphosphorylated tau protein in the form of neurofibrillary tangles, neuronal and synaptic loss, and cerebrovascular dysfunction (Jack et al, 2018). Since the cerebrovascular deficits develop very early in the AD process, it is detectable in individuals with mild cognitive impairment (MCI) and promote conversion from MCI to AD (Yetkin et al, 2006; Iadecola, 2010; Li et al, 2011). It has been widely reported that neurovascular coupling (NVC), a vasodilatory response to neuronal activity, is impaired in AD patients or animal models (Hock et al, 1997; Iadecola, 2004; Tong et al, 2012; Lourenço et al, 2017). The underlying mechanisms of NVC dysruption in the context of AD are still largely unknown

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