Cellular imaging of neurovascular breakdown in mixed models of Atherosclerosis and Alzheimer’s disease: The search for early biomarkers and targets for therapy.

Neurovascular coupling (NVC) is the mechanism responsible for regulating the supply of oxygen and glucose to active regions of the brain. Although our understanding of NVC mechanisms remains incomplete, investigations of NVC have recently taken on added importance. Accumulating evidence suggests that impaired NVC may be a significant causal component of age-related neurodegenerative disease1-3. Professor Zlokovic proposed that a breakdown of the neurovascular unit may be a causal factor in neurodegenerative disease4. However, thus far there have been few formal measurements of NVC function as disease pathology develops. In 2014, Alzheimer’s Research UK funded Dr Berwick’s laboratory to study early AD-associated changes in NVC. Using our chronic imaging capability we characterised the breakdown of neurovascular function at specific time points during the development of AD in a pre-clinical model (J20-AD). Surprisingly, and contrary to previous reports of significant impairments in the J20-AD model5-7, we found that the typical hemodynamic response to sensory stimulation was largely unaltered8.These observations suggest that the disease state in the J20-AD model may be rather more nuanced than suggested previously. We are therefore proposing a more sophisticated approach in which milder (J20-AD) and more aggressive (APP-PS1) pre-clinical models of AD (colonies already in Sheffield) are combined with a model of Atherosclerosis (ATH). In the case of human AD cerebrovascular and cardiovascular dysfunction are frequently treated separately. However, the potentially modifying effects of a compromised peripheral vascular physiology on central neurovascular function should not be overlooked9. Gorelick et al10 specifically highlighted the need for more information about how cardiovascular disease might affect the progression of AD. Our recently published review11 also focused on the need for a greater understanding of how cardiovascular disease might affect cerebrovascular health. Working with Professor Sheila Francis we have produced an ATH-like condition in the J20-AD model. This was achieved by reducing Low Density Lipoprotein (LDL) receptor expression using a systemic injection of modifying AAV8 vector followed by a high fat diet12. In these experiments we found evidence of neurovascular compromise at 8 weeks following the AAV injection and high fat diet. Specifically, the cortical hemodynamic response to sensory stimulation, measured by 2-dimensional optical imaging spectroscopy (2D-OIS), was substantially reduced. Although 2D-OIS is a good technique to measure brain responses over a large cortical area it does not have the resolution needed to investigate cellular mechanisms of neurovascular pathology. Therefore the main focus of this PhD project will be to employ high resolution in-vivo 2-photon imaging (led by Dr Howarth) in the novel mixed pre-clinical models of AD and ATH to investigate which cells of the neurovascular unit contribute to the pathology seen in the lower resolution optical imaging experiments.
References: 1 Iadecola, Neuron 80, 844-866, (2013). 2 Zlokovic, Trends in neurosciences 28, 202-208, (2005). 3 Zlokovic, Nature reviews. Neuroscience 12, 723-738,(2011). 4 Zlokovic, Nature medicine 16, 1370-1371,(2010). 5 Lacoste, et al, J of neuroinflammation 10, 57,(2013). 6 Ongali, et al. Neurobiology of disease 68, 126-136,(2014). 7 Royea, et al J of neuroscience 37, 5562-5573,(2017). 8 Sharp, et al . JCBFM (2019). 9 Girouard & Iadecola, Journal of applied physiology 100, 328-335, (2006). 10 Gorelick et al. Stroke; 42, 2672-2713, (2011). 11 Shabir, et al BMC neuroscience 19, 62, (2018). 12 Bjorklund, et al. Circ Res 114, 1684-1689, (2014)