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

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.

Behavioral and Neural Activity-Dependent Recanalization of Plugged Capillaries in the Brain of Adult and Aged Mice

“…This may explain the surprising finding that leukocyte based capillary obstructions were not improved by exercise in an Alzheimer's mouse model (Falkenhain et al, 2020). However, Alzheimer's disease is also associated with abnormal cortical excitability and NVC (Park et al, 2020, p. 202;Li et al, 2021;Shabir et al, 2022), therefore exercise may not have sufficiently engaged NVC signaling pathways to overcome capillary stalling. Nonetheless, whether the present findings will have utility in clearing naturally occurring obstructions in aging or disease states where inflammatory factors are in play, remains to be determined.…”

Aberrant energy metabolism in Alzheimer’s disease

“…[64] Functional hyperemia, which disturbs neurodegeneration, is also perturbed in AD. [65,66] In the adult brains of animals and humans, neurogenesis is mainly located in the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus. [67][68][69] Hippocampal neurogenesis contributes to the progression of learning and memory and inhibition of neurogenesis hampers trace-related memory formation.…”

Assaying activity-dependent arteriole and capillary responses in brain slices

“…The NVC response is imperative for healthy brain function, but changes during development 6 , 38 and in the context of several neurological diseases. 13 , 39 – 42 Although these conditions must be understood, ultimately, in the in vivo context, drug delivery to the brain for refined in vivo pharmacology studies can be challenging. Furthermore, it is difficult to distinguish in vivo the active, local response of different vascular segments from passive effects due to changes in flow or pressure within that vascular tree.…”

“…We describe how to concurrently monitor electrically stimulated neuronal activity and the subsequent change in vascular diameter, with emphasis on proper placement of electrodes near the blood vessel to ensure regional neuronal activation without direct vessel stimulation. We discuss these methods in the context of the cerebral cortex, however, similar approaches can be easily adapted for other brain regions such as the hippocampus 13 and cerebellum. 14 …”