CoEN5025 NANOSYN: Unravelling synaptic pathology in Alzheimer's disease and Dementia with Lewy bodies using super-resolution microscopy
Lead Research Organisation:
University of Edinburgh
Department Name: Centre for Discovery Brain Sciences
Abstract
Alzheimer's disease (AD) and Dementia with Lewy bodies (DLB) are the two most common causes of dementia. In order to find effective treatments, it is critical that we understand the exact causes. Accumulation of Abeta and tau proteins in the brain occurs early in people with AD. In DLB, a protein called alpha-synuclein accumulates early inside neurons. We know that synapses, the most critical structures for communication between neurons, are lost very early in these diseases. However, the precise mechanism by which these proteins damage synapses is poorly understood due to the lack of adequate techniques. Here, we will apply the most advanced tools available to investigate the presence of abnormal proteins at synapses in a unique set of human brain samples. We will also investigate the effects of toxic proteins on synapse composition. This information will be invaluable for the development of more specific treatments for the two most common causes of dementia.
Technical Summary
Alzheimer's disease (AD) and Dementia with Lewy bodies (DLB) are the two most common causes of dementia, characterized by neuronal loss and abnormal protein aggregates. In AD, the pathological hallmarks are extracellular aggregates of amyloid beta (Ab) and intracellular aggregates of hyperphosphorylated tau (ptau). In DLB, the hallmark is aggregated alpha-synuclein (alpha-syn) in the neuronal soma and processes. Synapse loss is an early and key feature in both diseases. However, the characterization of synaptic damage in humans has remained elusive due to the lack of sensitive techniques to resolve these small structures. In this project, we will apply 2 super-resolution microscopy techniques (Array Tomography [AT] and Single-Molecule Localization super-resolution Microscopy [SMLM] approaches, such as STORM and DNA-PAINT) to systematically investigate synaptic damage in single synapses in 5 human brain regions affected by AD and DLB pathology. We will use a unique collection of human brain samples collected in Edinburgh and Barcelona ready for AT/SMLM. We will compare the localization of oligomeric and fibrillar forms of Ab, ptau and alpha-syn at millions of synapses across several brain regions. This project will apply the latest technology to unravel this key phenomenon and could lead to the development of more specific treatments aimed at restoring synapses in these common dementias.
Organisations
Publications
Tzioras M
(2023)
Synaptic degeneration in Alzheimer disease.
in Nature reviews. Neurology
Kurucu H
(2021)
Inhibitory synapse loss and accumulation of amyloid beta in inhibitory presynaptic terminals in Alzheimer's disease
in European Journal of Neurology
Izzo NJ
(2020)
Proceedings from the Fourth International Symposium on s-2 Receptors: Role in Health and Disease.
in eNeuro
Colom-Cadena M
(2020)
The clinical promise of biomarkers of synapse damage or loss in Alzheimer's disease.
in Alzheimer's research & therapy
Colom-Cadena M
(2023)
Synaptic oligomeric tau in Alzheimer's disease - A potential culprit in the spread of tau pathology through the brain.
in Neuron
Description | Invited Panel Member in European Alzheimer's Roundtable - International Centre for Parliamentary Studies |
Geographic Reach | Europe |
Policy Influence Type | Membership of a guideline committee |
URL | https://government-gazette.parlicentre.org/ |
Description | Translational Neuroscience 2 (TN2) |
Amount | £5,509,212 (GBP) |
Funding ID | 218493/Z/19/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2020 |
End | 09/2028 |
Title | Image analysis macros for array tomography |
Description | The MATLAB and image J scripts provided here were used to analyse array tomography image stacks in the study "Reducing tau ameliorates behavioural and transcriptional deficits in a novel model of Alzheimer's disease" by Pickett et al (https://doi.org/10.1101/393405 ). I |
Type Of Material | Computer model/algorithm |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | we have taught international groups how to use these macros which helped result in future funding |
URL | https://datashare.ed.ac.uk/handle/10283/3380 |
Description | BBC Radio Ulster interview |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Participation in a radio interview about dementia research on BBC radio Ulster 27 Sept 2020 |
Year(s) Of Engagement Activity | 2020 |
Description | Lab Notes - Alzheimer's Research UK |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | LabNotes webinar and YouTube video: Connections are key - targeting synapses to treat Alzheimer's (75 attendees live, >300 YouTube views). Hosted by Alzheimer's research UK |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.youtube.com/watch?v=oWCLQRcRP58&t=2607s |
Description | Webinar - Genes, Lifestyle, and dementias |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Webinar - Genes and lifestyle influence risks of dementia including dementia associated with Huntington's disease. Organised by the Huntington's Disease Association. |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.hda.org.uk/events/genes-and-lifestyle-influence-causes-of-dementia-including-huntingtons... |