University Of Bristol Kei Cho
Synaptic Plasticity and Alzheimer’s Disease
Alzheimer’s disease (AD) is the leading form of dementia; a progressive, neurodegenerative disease that is incurable with currently available therapeutic approaches. The pathology of AD has been classically characterized in its late stages by significant neuronal cell death linked to aberrant enzyme regulation, plaques of amyloid-beta (Aβ) and neurofibrillary tangles of tau. It has become increasingly evident that AD has its origins embedded at the neuronal synapse. Indeed, it is now widely accepted that synaptic dysfunction, which is manifest in the emergence of aberrant synaptic plasticity, is a major pathophysiological consequence of AD. The Cho group seminally characterised a novel underlying mechanism of long-term depression (LTD) of synaptic efficacy (also known as a form of synaptic elimination). Here, the caspase-mediated cleavage of Akt-1 forms part of a hippocampal LTD mechanism, ultimately leading to AMPAR endocytosis (Cell (2010) 141, 859-871). The Cho group later demonstrated that the caspase-Akt1-GSK-3β cascade is involved in Aβ-mediated pathophysiological synaptic dysfunction in the hippocampus (Nature Neuroscience (2011) 14, 545-547). Work in the Cho group continues to determine how aberrant synaptic elimination is expressed and what the physiological and pathological consequences might be. Therefore, discovering the mechanisms underlying how Aβ/tau causes pathophysiology will likely contribute to development of therapeutic interventions for Aβ/tau toxicity.
The plastic nature of synapses means that long-term potentiation (LTP, a prolonged increase in synaptic transmission) and long-term depression (LTD, a long-lasting depression of synaptic transmission) can be induced.
Using brain slice electrophysiology and calcium imaging techniques, our findings from the hippocampus and perirhinal cortex have suggested a new form of LTD in which G-protein coupled metabotropic glutamate receptors (mGluRs) have an important role. These findings have led to a greater understanding of mechanisms that regulate mGluRs and the ways in which mGluRs interact with other receptors. Our group is also investigating the molecular roles of postsynaptic calcium sensors and caspase-cascades in hippocampal and perirhinal LTP.
- excitatory synapse
- long-term synaptic plasticity
- brain atrophy
Diseases related to this field of research
- Alzheimer’s disease
- Amyloid-beta toxicity
Processes and functions relevant to this work
- Synaptic Plasticity
- Recogntion Memory
- Stem-cell differentiation