Neurovascular coupling is a critical brain mechanism whereby changes to blood flow accompany localised neural activity. The breakdown of neurovascular coupling is linked to the development and progression of several neurological conditions including dementia. In this study, we examined cortical haemodynamics in mouse preparations that modelled Alzheimer’s disease (J20-AD) and atherosclerosis (PCSK9-ATH) between 9 and 12 m of age. We report novel findings with atherosclerosis where neurovascular decline is characterised by significantly reduced blood volume, altered levels of oxyhaemoglobin and deoxyhaemoglobin, in addition to global neuroinflammation. In the comorbid mixed model (J20-PCSK9-MIX), we report a 3 x increase in hippocampal amyloid-beta plaques. A key finding was that cortical spreading depression (CSD) due to electrode insertion into the brain was worse in the diseased animals and led to a prolonged period of hypoxia. These findings suggest that systemic atherosclerosis can be detrimental to neurovascular health and that having cardiovascular comorbidities can exacerbate pre-existing Alzheimer’s-related amyloid-plaques.

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, ...

AbstractEarly 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 6-9 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 by driving an increased baseline blood flow to the brain, thereby potentially enhancing the clearance of beta-amyloid.

Neurovascular coupling is a critical brain mechanism whereby changes to blood flow accompany localised neural activity. The breakdown of neurovascular coupling is linked to the development and progression of several neurological conditions including dementia. However, experimental data commonly arise from preclinical models in young mice with one disease only. In this study, we examined cortical haemodynamics in preparations that modelled common co-existing conditions namely Alzheimer's disease (J20-AD) combined with atherosclerosis (PCSK9-ATH) between 9-12m of age. We report novel findings with atherosclerosis where neurovascular decline is characterised by significantly reduced blood volume (HbT), levels of oxyhaemoglobin (HbO) & deoxyhaemoglobin (HbR), in addition to global neuroinflammation. In the comorbid mixed model (J20-PCSK9-MIX), we report a highly significant increase (3x fold) in hippocampal amyloid-beta plaques, without any further alterations to neurovascular function. There were no significant changes in evoked neural activity in any of the disease models, suggesting a breakdown of neurovascular coupling in PCSK9-ATH mice with inadequate oxygen delivery. A key finding was that cortical spreading depression (CSD) due to electrode insertion into the brain was worse in the diseased animals and led to a prolonged period of hypoxia and potentially ischaemia. The inflammatory environment in the brain was also perturbed, with interleukin-1 beta raised up to 2-fold and tumour necrosis factor raised up to 7-fold in brain tissues from these mice. Taken together, these findings suggest that systemic atherosclerosis can be detrimental to neurovascular health and that having cardiovascular comorbidities can exacerbate pre-existing Alzheimer's-related amyloid-plaques.