Abstract
Early impairments to neurovascular coupling have been proposed to be a key pathogenic factor in the onset and progression of Alzheimer’s disease (AD). Studies have shown impaired neurovascular function in several mouse models of AD, including the J20-hAPP mouse. In this study, we aimed to investigate early neurovascular changes using wild-type (WT) controls and J20-hAPP mice at 6 months of age, by measuring cerebral haemodynamics and neural activity to physiological sensory stimulations. A thinned cranial window was prepared to allow access to cortical vasculature and imaged using 2D-optical imaging spectroscopy (2D-OIS). After chronic imaging sessions where the skull was intact, a terminal acute imaging session was performed where an electrode was inserted into the brain to record simultaneous neural activity. We found that cerebral haemodynamic changes were significantly enhanced in J20-hAPP mice compared with controls in response to physiological stimulations, potentially due to the significantly higher neural activity (hyperexcitability) seen in the J20-hAPP mice. Thus, neurovascular coupling remained preserved under a chronic imaging preparation. Further, under hyperoxia, the baseline blood volume and saturation of all vascular compartments in the brains of J20-hAPP mice were substantially enhanced compared to WT controls, but this effect disappeared under normoxic conditions. This study highlights novel findings not previously seen in the J20-hAPP mouse model, and may point towards a potential therapeutic strategy.
Highlights
Impairments to neurovascular coupling have been proposed to be a key pathogenic factor in the onset and progression of Alzheimer’s disease (AD)
A week after chronic imaging sessions, a small burr-hole was drilled through the skull in the centre of the barrel cortex; determined from 2D-optical imaging spectroscopy (2D-OIS) data on a previous chronic imaging session, and a micro-electrode was inserted through the brain as a terminal experiment (Fig. 1, bottom row)
Using the chronic thinned cranial window preparation and imaging through an intact skull 2 weeks after surgery, the first question addressed was whether stimulation-evoked haemodynamic responses were different in J20-human amyloid precursor protein (hAPP) mice compared to WT controls
Summary
Impairments to neurovascular coupling have been proposed to be a key pathogenic factor in the onset and progression of Alzheimer’s disease (AD). We aimed to investigate early neurovascular changes using wild-type (WT) controls and J20-hAPP mice at 6 months of age, by measuring cerebral haemodynamics and neural activity to physiological sensory stimulations. Whilst numerous mouse models of AD exist, they do not fully recapitulate the human disease in its entirety[2,3] These mouse models can effectively model specific aspects of AD pathology, such as amyloid plaque deposition and toxicity where smaller oligomers (8-24-mers) have been shown to be more toxic than larger matured fibrils[4]. The J20-hAPP mouse model of AD over-expresses human amyloid precursor protein (hAPP) with the Swedish (K670N and M671L) and the Indiana (V7171F) familial mutations[5] These mice produce more Aβ1-42 and plaques begin to readily form in the hippocampus from around 5–6 months of age[5,6]. Studying neurovascular coupling and neurovascular degeneration is important to identify early biomarkers or treatment strategies
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