Neuronal and glial network activity in mouse models of Alzheimer's Disease.

Prevalence of neurodegenerative diseases continues to be on the rise, with 1 million people predicted to suffer from dementia by 2024 in the UK. Alzheimer's Disease (AD) is the main cause of dementia while also sharing a lot of its pathophysiology with other causes, making the understanding of its mechanism of disease a fundamental aim for the research community.

Several different factors are known to be involved in the development of AD. A hallmark of disease is the accumulation in the brain of dysfunctional proteins amyloid beta and phosphorylated tau. From a cellular perspective, both are implicated in pathways culminating in neuronal toxicity and ultimately neurodegeneration. These pathways also see the involvement of microglia and astrocytes, which exacerbate neurodegeneration through the initiation and maintenance of inflammation. The impact of the accumulation of amyloid beta and phosphorylated tau on neurons and glia is currently much better understood at a cellular and molecular level, while little is known about how they affect the overall function of the intact brain.

To address this gap in the existing literature on AD, I want to develop and carry out experiments aimed at detecting the interplay, at the network level, between astrocytes and neurons and how it is affected by the accumulation of amyloid beta plaques and phosphorylated tau tangles in Alzheimer's mouse models. In the first year of my study, in preparation for my upgrade from MPhil to PhD, I plan to thoroughly delve into the relevant literature, and informed by it, undertake experiments that will allow me to master the techniques needed for the project as well as take concrete steps towards my thesis goals.

Electrophysiological measurements such as electroencephalograms (EEG) and local field potential (LFP) appear to offer a reliable read-out for dysfunction in neural networks and are altered in humans suffering dementia or mild cognitive impairment, as well as in animal models of these disorders. Astrocyte activity cannot be captured with by conventional electrophysiological techniques but can be captured by calcium imaging. To investigate the interplay between neuronal networks and astrocyte activity in health and disease, I therefore aim to adopt a multi-level approach to circuit function in awake animals, combining electrophysiology with calcium imaging. I would like to start implementing this approach in the context of experimental designs that include the presentation of visual stimuli and the recording from primary visual cortex (V1) and other areas of head-fixed mice, initially in wild-type and subsequently in relevant Tau/Amyloid Beta models. From a technical perspective this would involve viral injections into the relevant brain area to express GCaMP in neuronal or astrocyte populations, with subsequent implantation of an optic fiber to record calcium signals and nearby LFP probe(s) to record electrical signals. I am looking forward to the data collected in my first year to further inform the overall direction of my study to ultimately contribute to the understanding of how neuronal and glial networks are affected in Alzheimer's Disease.