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. 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.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia worldwide, with the vast majority of cases being sporadic and occurring at age 65 years and over
A small burr-hole was drilled through the thinned skull overlying the active region of interest (ROI) as determined from the chronic imaging sessions (Figure 1D), and a Neuroscience multichannel electrode was inserted into the brain (Figure 1E) to record neural activity simultaneously
The present study investigated neurovascular function in a novel experimental model of atherosclerosis (PCSK9-ATH) and for the first time, in a comorbid setting whereby atherosclerosis was experimentally induced in a well characterised model of AD; J20-human amyloid precursor protein (hAPP), to create a mixed comorbid model (J20-PCSK9-MIX)
Summary
Alzheimer’s disease (AD) is the most common form of dementia worldwide, with the vast majority of cases being sporadic and occurring at age 65 years and over. A major cardiovascular pathology that affects as many as up to 60% of all individuals after the age of 55 is atherosclerosis. There is evidence that, do these often exist as comorbidities, but they may interact pathogenically with vascular disease and neurovascular unit changes contributing to AD (Iadecola, 2017; Kapasi and Schneider, 2016). The vascular cognitive impairment (VCI) which precedes the onset of dementia may be attributed to a variety of different vascular pathologies affecting either systemic or intracranial vasculature (both large or small vessels) (Iadecola et al, 2019). Due to the complexity of atherosclerosis and dementia pathogenesis, understanding the mechanisms of their mutual interactions is necessary if efforts to develop therapeutics to prevent VCI and vascular dementia, which currently has no disease-modifying cure, are to succeed
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