Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.13.249987v1?rss=1 Authors: Shabir, O., Pendry, B., Lee, L. M., Eyre, B., Sharp, P., Rebollar, M. A., Howarth, C., Heath, P. R., Wharton, S. B., Francis, S., Berwick, J. Abstract: 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. Copy rights belong to original authors. Visit the link for more info