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

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. Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is characterised by a progressive decline in cognition. AD is pathologically characterised by the presence of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated-tau, which are associated with the progressive neurodegeneration and synaptic dysfunction seen in AD 1. At present there are limited disease modifying or curative treatments for AD and studying disease mechanisms in human subjects is difficult. Therefore, pre-clinical models of AD; mainly mouse models, have been generated to study AD mechanisms in vivo. Whilst numerous mouse models of AD exist, they do not fully recapitulate the human disease in its entirety 2,3. However, 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. The J20-hAPP mouse model displays significant neuroinflammation characterised by gliosis of both astrocytes and microglia 6. They also display significant long-term memory impairment 6. The brain is extremely metabolically demanding, ...

Hyperbaric oxygen therapy alleviates vascular dysfunction and amyloid burden in an Alzheimer’s disease mouse model and in elderly patients

“…HBOT has also been shown to increase CBF and improve EEG measurements [ 34 ], global cognitive scores [ 33 , 69 ] and PET scans [ 70 ] of post-stroke and TBI patients. In the context of Alzheimer’s disease, animal studies have shown that supplementation of oxygen [ 71 , 72 ] or HBOT [ 17 , 36 ] results in improved cognitive performance [ 71 ] and enhanced cerebral blood volume [ 72 ]. Moreover, an immediate increase in CBF due to a reduction in the number of stalled capillaries led to rapid improvement in the performance of 5XFAD mice in spatial and working memory tasks [ 15 ].…”

Assessment of Neurovascular Coupling & Cortical Spreading Depression in Mixed Models of Atherosclerosis & Alzheimer’s Disease

“…We performed chronic imaging of the brain cortex 3-weeks post-surgery, where the thinned cranial window remained intact (Figure 1A/B), as described previously (Shabir et al, 2020; Sharp et al, 2019). We deployed a range of stimulations (2s & 16s mechanical whisker stimulations) with the mouse breathing both 100% oxygen (hyperoxia) and 21% oxygen (normoxia), in addition to recording transitions between conditions and performing a 10% hypercapnia test to test the maximum dilation of vessels.…”

“…We performed chronic imaging of the brain cortex 3-weeks post-surgery, where the thinned cranial window remained intact (Figure 1A/B), as described previously (Shabir et al, 2020;Sharp et al, 2019).…”

Cerebrovascular development: mechanisms and experimental approaches

“…Still, imaging of the intracerebral vasculature technically challenging, requiring a surgically-created cranial window. Imaging the cerebral vessels is now possible for several weeks [ 23 – 25 ], with greater imaging depth achieved by 3‐photon fluorescence microscopy [ 26 ] and long wavelength reflectance confocal microscopy [ 27 ]. Despite such improvements in vivo imaging, most rodent studies of cerebral vessels remain histological.…”