Neurovascular coupling preserved in a chronic mouse model of Alzheimer’s disease: Methodology is critical

Abstract

Significance Statement (115/120 words)Using a chronic anaesthetised preparation, we measured hemodynamic responses evoked by sensory stimulation and respiratory gases in the J20-AD mouse model of Alzheimer's Disease over a period of 3 months. We showed that neurovascular responses were preserved compared to age matched wildtype controls. These results failed to confirm previous investigations reporting a marked reduction of neurovascular coupling in the J20-AD mouse model. However, when our procedure involved acute surgical procedures, previously reported neurovascular deficits were observed. The effects of acute electrode implantation were caused by disturbances to baseline physiology rather than a consequence of the disease condition. These results highlight the importance of experimental procedure when determining the characteristics of animal models of human disease. Abstract (243/250 words)Neurovascular coupling is the process by which neural activity causes localised changes in cerebral blood flow. Impaired neurovascular coupling has been suggested as an early pathogenic factor in Alzheimer's disease (AD), and if so, could serve as an early biomarker of cerebral pathology. We have established an anaesthetic regime in which evoked hemodynamic responses are comparable to those in awake mice. This protocol was adapted to allow repeated measurements of neurovascular function over three months in the hAPP-J20 mouse model of AD (J20-AD) and wild-type (WT) controls. Animals were 9-12 months old at the start of the experiment, which is when deficits due to the disease condition would be expected.Mice were chronically prepared with a cranial window through which optical imaging spectroscopy (OIS) was used to generate functional maps of the cerebral blood volume and saturation changes evoked by whisker stimulation and vascular reactivity challenges. Unexpectedly, the hemodynamic responses were largely preserved in the J20-AD group. This result failed to confirm previous investigations using the J20-AD model. However, a final acute electrophysiology and OIS experiment was performed to measure both neural and hemodynamic responses concurrently. In this experiment, previously reported deficits in neurovascular coupling in the J20-AD model were observed. This suggests that J20-AD mice may be more susceptible to the physiologically stressing conditions of an acute experimental procedure compared to WT animals. These results therefore highlight the importance of experimental procedure when determining the characteristics of animal models of human disease.

Enhanced Cerebral Blood Volume under Normobaric Hyperoxia in the J20-hAPP Mouse Model of Alzheimer’s Disease

“…As such, despite the enhanced MUA seen in our J20-hAPP mice to stimulations, the haemodynamics measured are comparable to WT controls due to CSD. Although cerebral haemodynamics recover in both WT and J20-hAPP mice, the rate of recovery between these varies, and J20-hAPP mice take longer as previously demonstrated 10 . By the end of the experimental period (16s-stimulaton 100% O 2 ), HbT increases in J20-hAPP mice to match that of WT controls (Fig.…”

“…Our data along with others investigating neural activity confirm that there is neuronal hyperexcitability around 6 m of age in the J20-hAPP mouse, but that there is no difference in vascular reactivity between WT controls and J20-hAPP mice as demonstrated by the response to hypercapnia. Previous research from our laboratory has shown no significant differences in either haemodynamics or neural activity between 9-12 m in the same J20-mouse model unless an electrode is inserted into the brain 10 . Using exactly the same approach, we present here novel findings of hyperexcitability and enhanced evoked haemodynamic responses at an earlier age, around 6 m, in the J20-mouse model of AD.…”

“…Using a chronic mouse preparation, previous research from our laboratory found no significant neurovascular deficits in the J20-hAPP mouse between 9-12 m age 10 , despite neuroinflammation and memory deficits 6 . This is contrary to what other laboratories have shown with the J20-mouse at the same age [11][12][13] .…”

“…S2). As described in our previous research using the J20-hAPP mouse between 9-12 m of age 10 , insertion of an electrode into the mouse brain can cause cortical spreading depression (CSD) to occur across the cortex 31 . CSD is characterised by prolonged vasoconstriction that can persist for some time (in some cases over an hour) and this generally dampens haemodynamic responses and overall cerebral blood flow across a wide area of the cerebral cortex 32 .…”

Pathological changes in neurovascular units: Lessons from cases of vascular dementia

“…VD pathogenesis involves the following three mechanisms: (1) the decrease of CBF leads to the disturbance of energy supply to the brain, resulting in neuronal dysfunction and a series of stress reactions such as inflammation, exacerbating the neuronal damage; (2) glial cells which normally play a supporting and nutritive role in central nervous system (CNS) undergo abnormal activation and damage induced by ischemia, hypoxia and neuroinflammation; and (3) ischemia and hypoxia lead to vascular permeability changes and vascular endothelial injury 21 . Interestingly, even in VD patients with cerebral cortical microinfarcts, global decrease in CBF is noted but perfusion around the infarction is not affected, 22 suggesting wide‐spread NVU damage rather than local perfusion failure.…”