Deanery of Biomedical Sciences
Alzheimer’s disease (AD) is the most common form of dementia impairing memory and affecting over 50 million people worldwide, including 850,000 people in the UK. Unfortunately, there is currently no cure for AD and all therapeutics targeting the underlying mechanisms (e.g. amyloid plaque pathology) have failed in numerous clinical trials. These disappointing outcomes have highlighted the need to find alternative and more integrated strategies to counteract the disease.
In this light, this project will focus on the homeostatic compensatory mechanisms of the brain that cope with the effects of pathology rather than with the development of the pathology itself. In particular, we will focus on the compensatory mechanisms of the brain counteracting the loss of synapses – the point of communication between neurons- occurring at the earliest stages of Alzheimer’s disease and that are strongly associated with the emergence of cognitive deficits.
The main objective of this proposal is to understand the molecular and cellular mechanisms underlying these compensatory mechanisms - with the ultimately goal of boosting them to prevent the onset of cognitive deficits.
Because synaptic loss in AD occurs randomly, we have recently developed a molecular tool to artificially eliminate synapses to model this crucial aspect of AD. In this project, we will take advantage of this optical tool to promote the artificial elimination of synapse - with high spatiotemporal control - in order to visualize the emergence of compensation over time using in-vitro and in-vivo two-photon microscopy in organotypic hippocampal slice cultures and in cortical regions of the brain, respectively. Second, we will investigate the molecular mechanisms underlying these compensatory events using transcriptomic and proteomics approaches. Finally, we will examine whether boosting key molecular players underlying these compensatory mechanisms in mouse model of Alzheimer’s disease to prevent synaptic loss and cognitive deficits.
Together, the knowledge gained in this project will not only reveal the inherent homeostatic capabilities of the brain counteracting synaptic loss but will also be instrumental in identifying innovatives and complementaries therapeutic against cognitive decline in AD.