Identifying vulnerable synaptic components for synaptotherapeutic intervention

One in four NHS hospital beds are occupied by someone with dementia with the annual UK economic cost of dementia being £26 billion. However, we are now at a pivotal moment in Alzheimer's Disease (AD) research. With the recent positive results from clinical trials, the prospect of finding a disease-modifying therapy to alter disease progression and slow cognitive decline is nearing a reality.

Synaptotherapies aim to further restore cognitive function in combination with other therapies to alleviate the impact of dementia on society. As the loss of synapses closely correlates with cognitive decline in AD, it is imperative that the mechanisms of synaptopathy are understood to develop a synapse-targeting treatment. 

The Jackson team has previously shown that pre- and post-synaptic components are differentially affected in preclinical models of tauopathy and amyloidopathy. In human tissue, the group has characterised the laminar-specific loss of synaptic proteins and shown changes in nuclear expression of synaptic RNA transcripts in AD. More recently, they have identified diferentially expressed synaptic proteins along a pseudotemporal profile and a peri-synaptic astrocytic signature that is associated with synapse loss. Furthermore, the team have provided evidence of glial and synaptic changes associated with disease progression rate and characterised the cellular distribution of a synaptic biomarker target.

The Jackson group takes a multi-‘omic and imaging approach to provide a mechanistic insight into the vulnerability of synaptic components in neurodegeneration. Their work uses a number of methodologies such as synaptic proteomics and transcriptomics, mass synaptometry and advanced imaging techniques such two-photon imaging and imaging mass cytometry. These are primarily conducted in human tissue but supported by collaborative work using iPSCs and preclinical models for target perturbation.