Synaptic pathology in ALS-FTD

Dementia will affect 1 in 3 people in their lifetime. The inexorable decline in mental function, mood and movement ability comes about because of damage to synapses - the connections between nerve cells. Synapses come in many varieties and particular types are affected as dementia progresses. By finding and tracking these damaged synapses we can understand how the brain is damaged in dementia and help to bring on improvements in the diagnosis and treatment of these diseases.

We have recently developed ground-breaking technology that enables us to examine billions of individual synapses in the human brain and discover how the are damaged. We will now drive this technology forward to discover the synapses that are damaged in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS, or motor neuron disease, is a rapidly progressive, fatal condition which overlaps clinically, genetically and pathologically with frontotemporal dementia (FTD). ALS-FTD are the commonest forms of neurodegenerative disease in people under 65 years of age.

Our team of scientists from the UK and Japan will use several state-of-the-art microscopy methods to examine synapses in post-mortem brain tissue obtained from individuals who have had their behavioural features examined during life. This will potentially enable us to identify the synapses that when damaged cause speech and language impairments, deterioration in mood and emotions, and movement disorders.

The tools and knowledge from our program will inform on the use of brain imaging methods in the clinic and trials of therapies aimed at preventing the progression of ALS-FTD and other dementias. Our findings will also provide valuable data resources that can be exploited by the international scientific community to advance our understanding of the brain and its diseases,

Synapse loss and damage is a hallmark of neurodegenerative disease. New molecular imaging methods reveal that there is a far greater diversity of synapse types than previously known, and that these are spatially distributed across nerve cells, brain regions and the whole brain into a remarkable spatial organisation. This 'synaptome architecture' provides a roadmap for understanding how molecular perturbations, such as genetic disorders, pathogenic proteins and drug interactions, can impact on specific synapses, circuits and brain regions. Crucially, we know that specific types of synapses - some are vulnerable, whereas others are resistant - are targeted in neurological disease. Although synapse loss in neurodegenerative disorders is well documented, very little is known about the nature of vulnerable and resilient synapses and how they are involved in the behavioural features of dementia. To address this, we will study the synaptome architecture of Amyotrophic Lateral Sclerosis (ALS) and Fronto-Temporal Dementia (FTD), which share clinical, genetic and pathological features.

We will use a collection of samples from ALS-FTD cases that were characterised in life with the Edinburgh Cognitive and Behavioural ALS Screen. Four brain regions aligned to executive and language functions have been selected, allowing the synaptic pathology of specific brain areas to be correlated with behavioural phenotypes. The molecular and morphological properties of synapses from 75 ALS-FTD cases and 10 age-matched controls will be examined with multiple complementary microscopy platforms (high throughput spinning disk confocal microscopy, expansion microscopy, super-resolution microscopy, and electron microscopy), which together are capable of characterising billions of individual synapses and resolving their architecture at nanoscale resolution. The protocols and tools developed can be applied to the study of synapse pathology in any brain disease.