Developing chronic implants for the treatment of Alzheimer's disease in pre-clinical models

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 taken on added importance. Accumulating evidence suggests that impaired NVC may be a significant causal component of age-related neurodegenerative disease especially Alzheimer's Disease (AD) (Iadecola, 2013; Zlokovic, 2010, 2011). Professor Zlokovic proposed that a breakdown of the neurovascular unit may be a causal factor in neurodegenerative disease (Zlokovic, 2010). 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 chronic imaging capability, we characterised the breakdown of neurovascular function at specific time points during the development of AD in a mouse model (J20-AD). Surprisingly, and contrary to previous reports of significant impairments in the J20-AD model(Shabir et al., 2020; Sharp et al., 2019), we found that the typical hemodynamic response to sensory stimulation was largely unaltered in J20-AD mice. These observations suggest that the disease state in the J20-AD model may be rather more nuanced than suggested previously. We have started work on a more severe mouse model of Alzheimer's disease (APP/PS1) and have been performing a majority of experiments in the awake condition to avoid any confounds of anaesthesia. Traditionally, most research has used a pharmacological approach to treat AD aimed at reducing the amount of Beta-Amyloid plaques in the brain. However, no disease altering therapy has been developed yet, despite 40+ years of research. Other potential therapies need to be considered and developed. A key focus of our group is to develop new methods to treat AD. The first approach is to enhance baseline blood flow using optogenetics. AD patients suffer from chronic hypoperfusion, which is also present in the mouse models of AD we use. We have recently published results (Lee et al., 2019) whereby baseline blood flow could be increased by using an optogenetic approach to selectively activate cortical interneurons. However, we need an implantable system in order to deliver this light stimulation on a daily basis. The second approach will be to investigate the effect of selective thermal cooling of the brain on disease progression. Our laboratory has previously used thermal cooling to reduce the effects of focal cortical epilepsy, and it has recently been shown that cooling could have a marked effect on AD. It is hypothesised that repeated cooling of the animal increases its thermoregulatory response (Peretti et al., 2015; Tournissac et al., 2019), which then provides neuroprotection against neurodegeneration. To date there has been no research to assess if focal brain cooling could have a similar effect. Again, we need an implantable system that can deliver thermal cooling on a regular daily basis. Professor Minev is developing devices that can be implanted into the rodent brain and can deliver both thermal cooling and optogenetic stimulation. These devices will be transparent, allowing simultaneous imaging of the brain surface during cooling/stimulation. This project will focus on developing these implants for use in APP/PS1 mice in order to assess whether cooling/stimulation of interneurons has a therapeutic effect.