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The EMI's Synaptic Health theme is investigating the role of synapses in people with, or at risk of, dementia. These critical connections between brain cells are damaged early in the development of many different forms of cognitive decline. Understanding synaptic health may be key to better treatments in the future. 

Background

OHBA_acquisition11_scan.JPGSynapses are the connections which carry information between brain cells (neurons). They are critical for thinking, memory, decision making, perception and movement. The loss and damage of synapses have been implicated in the development of Alzheimer's disease and other forms of dementia. They are an early indicator of the development of these conditions, with damage caused by the aggregation of proteins (tau and amyloid), neuroinflammation, and brain cells' response to other stressors including vascular changes.

DPUK's Synaptic Health theme aims to understand how synaptic changes lead to cognitive impairment, and how these differences can be measured in humans. To quantify the loss of synapses in people with Alzheimer's disease, other forms of dementia and mild cognitive impairment (and its impact on brain function and cognition), we are testing cutting-edge brain scanning methods and analysis of cerebrospinal fluid (the fluid around the brain, known as CSF). New types of brain scan to measure synapses and cognitive physiology have been developed by DPUK's leading research partners in universities and the pharmaceutical industry, including Janssen (Johnson & Johnson), AstraZeneca and Lilly. This research will identify new markers of synaptic health and function that are anticipated to play an important role in testing new treatment possibilities in early-stage clinical trials.

Workstreams

synaptic_5_jeremyyoung.jpgThe Synaptic Health theme has two major workstreams. The first assesses the relationship between the quality and function of synapses. We measure the number and distribution of these connections using a ligand (a biological molecule 'dye') that targets the synaptic vesicle glycoprotein 2A (SV2A). This protein is found on all synapses – more specifically on the brain cell that is sending information (called pre-synaptic). The ligand is measured by position emission tomography (PET) imaging.

The function of the brain, for information processing and memory, will be measured using a different type of scan called magnetoencephalography (MEG). MEG scanning records the activity across the whole brain 1,000 times per second. In addition, synaptic fragments that are released into CSF will be measured to assess how they relate to the loss of synapses as seen on brain scans. The complementary information from brain imaging and CSF analysis provides extra validation for the new research methods.

The second workstream of this theme focuses on the pressing need for identifying changes to synapses on the brain cell that receives the information – called post-synaptic. We aim to test a new ligand targeting the post-synaptic TARP γ8 AMPAR protein using positron emission tomography linked to magnetic resonance imaging (PET-MRI). This new ligand has been evaluated in pre-clinical research, with promise for identifying post-synaptic changes in Alzheimer's disease.

Get involved

A researcher looks at an image of a brain scanIf you are interested in volunteering to take part in our research, either as a healthy person or someone with a diagnosis of Alzheimer's disease, mild cognitive impairment or dementia with Lewy bodies, please contact the team at hf367@cam.ac.uk. You can also register with Join Dementia Research to volunteer for research studies in your area.

If you are a researcher and would like to know more about the Synaptic Health theme and how your institution might collaborate or access data, please contact hf367@cam.ac.uk.

Theme objectives

1. To assess whether the synaptic vesicle glycoprotein 2A (SV2A, detected by PET ligand) in people with Alzheimer's disease (including mild cognitive impairment) correlates with clinical decline, with sufficient sensitivity and reliability to support clinical trials.

2. To assess whether the products of synaptic breakdown in CSF reflect the density and degree of loss of synapses as measured by PET.

3. To assess whether post-synaptic levels of the transmembrane AMPA receptor regulatory protein (TARP γ8 AMPAR) are reduced in early Alzheimer's disease, and if this change correlates with memory impairments.

Current work packages

These research questions will be interrogated within two Synaptic Health work packages, carried out at several UK universities:

1. Synaptic loss and its functional consequences in early Alzheimer's disease, using pre-synaptic markers and magnetoencephalography (co-leads: Professor James Rowe, University of Cambridge; Dr John Isaac, Janssen)

2. Synaptic loss and its functional consequences in early Alzheimer's disease, using a new post-synaptic TARP γ8 AMPAR ligand (co-leads: Professor James Rowe, University of Cambridge; Dr John Isaac, Janssen)

Prof James RoweThe EMI's Synaptic Health theme is led by Professor James Rowe (University of Cambridge).