Professor Tara Keck, University College London
Professor Inna Slutsky, Tel Aviv University
Alzheimer’s disease (AD) and other age-related pathologies are becoming increasingly common in our ageing society, exposing a large deficit in effective treatments. Continued failures in clinical trials and the realization that early intervention may offer better therapeutic outcomes have triggered a conceptual shift from focusing on the late-stage AD pathology to the early-stage pathophysiology.
While numerous molecular factors impaired in AD have been studied, the principle underlying the transition from ‘silent’ signatures in neural circuits to clinically measured memory decline remains unknown. Professor Keck and Professor Slutsky propose that failures in firing homeostasis in cortico-hippocampal circuits and stability-plasticity imbalance are the driving force of early disease progression. As ageing is the major risk factor for the most common, sporadic AD, we will first study whether and how ageing affects homeostatic processes in two different circuits in vivo – the V1 primary visual cortex and the CA1 hippocampus. They will then explore the effect of familial AD (fAD) mutations on firing homeostasis in mouse models in vivo.
The researchers will utilize recent advances in optical imaging, bioengineering and electrophysiology to enable time-lapse, cell-type specific recordings of neuronal activities from large populations of neurons in vivo. Using these approaches, they will determine whether firing stability is compromised by ageing and fAD mutations and whether it is associated with memory decline at early AD stages.
The proposed research will clarify fundamental principles of AD biology and will offer novel conceptual and therapeutic approaches for AD patients. It aims to lead to understanding how the brain is able to adapt during ageing, but will also have translational benefits. It will identify metabolic drivers and specific targets that may rescue homeostatic failures that occur during fAD. Understanding these targets could have potential therapeutic benefits for preventing memory loss which given the prevalence of AD, would have enormous economic benefits.
The two labs will share technologies, experimental expertise and data to set up a platform for characterizing the effects of homeostatic firing failures in ageing and fAD. Each team will be responsible for specific aims in the proposal (see methodology), but will have scientists working for extended periods in both labs to ensure there is cross-talk and exchange among the staff.