Targeting the synapse in Alzheimer’s Disease

View the seminar recording here (Imperial College members) or contact k.hobson@imperial.ac.uk to request access.

Centre for Neurotechnology seminar from Johanna Jackson

Advanced Research Fellow, Department of Brain Sciences, Dementia Research Institute, Imperial College London

Talk title: Targeting the synapse in Alzheimer’s Disease

Abstract: Alzheimer’s Disease is characterised by the accumulation of misfolded proteins, namely amyloid and tau, however it is synapse loss which leads to the cognitive impairments associated with the disease.  Many studies have focussed on single time points to determine the effects of pathology on synapses however this does not inform on the plasticity of the synapses, that is how they behave in vivo as the pathology progresses.  Here we used in vivo two-photon microscopy to assess the temporal dynamics of axonal boutons and dendritic spines in mouse models of tauopathy¹ (rTg4510) and amyloidopathy² (J20).  This revealed that pre- and post-synaptic components are differentially affected in both AD models in response to pathology.  In the Tg4510 model, differences in the stability and turnover of axonal boutons and dendritic spines immediately prior to neurite degeneration was revealed.  Moreover, the dystrophic neurites could be partially rescued by transgene suppression.  Understanding the imbalance in the response of pre- and post-synaptic components is crucial for drug discovery studies targeting the synapse in Alzheimer’s Disease.  To investigate how sub-types of synapses are affected in human tissue, the Multi-‘omics Atlas Project, a UKDRI initiative to comprehensively map the pathology in human AD, will determine the synaptome changes using imaging and synaptic proteomics in human post mortem AD tissue.  The use of multiple brain regions and multiple stages of disease will enable a pseudotemporal profile of pathology and the associated synapse alterations to be determined.  These data will be compared to data from preclinical models to determine the functional implications of the human findings, to better inform preclinical drug discovery studies and to develop a therapeutic strategy to target synapses in Alzheimer’s Disease³. 

1.  Jackson, J. S. et al. Altered Synapse Stability in the Early Stages of Tauopathy. Cell Rep. 18, (2017).
2. Stephen, T.-L. et al. Imbalance in the response of pre- and post-synaptic components to amyloidopathy. Sci. Rep. 9, (2019).
3. Jackson, J. et al. Targeting the Synapse in Alzheimer’s Disease. Front. Neurosci. 13, 735 (2019).

Bio: I am currently leading the Multi-’omics Atlas Project (MAP) at the Dementia Research Institute based at Imperial.   This is a project to establish a comprehensive multi-‘omic atlas characterising the pathology of human Alzheimer’s Disease.  I am also the Athena Swan lead for the Department of Brain Sciences.  My background is in synapse biology and in vivo two-photon imaging of synapse changes and other cellular processes.

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