The big questions
Which molecular signatures distinguish vulnerable synapses and circuits from resilient ones, and what can this tell us about why some individuals maintain cognitive function despite significant pathological burden?
Not all synapses, circuits or individuals are equally affected by neurodegenerative pathology. We will use scalable synaptic profiling in human post-mortem brain, alongside mouse models and iPSC-derived neurons, to define the molecular signatures of vulnerable and resilient synaptic populations across disease stages. Our goal is to identify druggable pathways that preserve synaptic integrity, maintain cognitive function and potentially slow disease progression.
How do interactions between cortical and subcortical brain regions contribute to disease-related dysfunction, and can targeting network-level activity restore function or slow progression?
Much of the field has focused on local circuit interactions, leaving the contribution of long-range connectivity and deep brain nuclei poorly understood. We will combine world-leading expertise in circuit interrogation in animal models with non-invasive stimulation techniques in humans to understand how cortical and subcortical regions interact in disease, and to test whether modulating rhythmic activity and network coordination can improve brain function and resilience.
How do modifiable factors — including sleep, neuroinflammation, sex and ageing — shape circuit health, and can intervening on these pathways offer therapeutic benefit across neurodegenerative diseases?
Circuit function is shaped by factors beyond protein pathology, many of which are modifiable. We will investigate how sleep-dependent processes, glial activity, hormonal changes and ageing interact with disease pathology to influence circuit integrity. By identifying points of intervention across these shared mechanisms, we aim to develop strategies that cut across individual diseases and broaden the scope of what can be targeted therapeutically.
