Alzheimer\'s disease, the most common cause of dementia in older people, is a devastating condition that is becoming a public health crisis as our population ages. Despite great progress recently in Alzheimerâ€™s disease research, we have no disease modifying drugs and a decade...
Alzheimer\'s disease, the most common cause of dementia in older people, is a devastating condition that is becoming a public health crisis as our population ages. Despite great progress recently in Alzheimerâ€™s disease research, we have no disease modifying drugs and a decade with a 99.6% failure rate of clinical trials attempting to treat the disease. This project aims to develop relevant therapeutic targets to restore brain function in Alzheimerâ€™s disease by integrating human and model studies of synapses. We have known for many years that the proteins amyloid beta and tau clump abnormally in plaques and tangles in the brains of people with Alzheimerâ€™s disease. It is widely accepted in the field that alterations in amyloid beta initiate the disease process. However, the cascade leading from changes in amyloid to widespread tau protein pathology and brain cell death remain unclear. Loss of connections between brain cells called synapses is the best marker in the brain of the symptoms of Alzheimerâ€™s disease including memory and thinking problems. In this project, we are testing the idea that the brain changes in Alzheimerâ€™s disease leading from amyloid beta to tau to brain cell death and dementia symptoms begin in synapses. The team is using cutting edge imaging technology to examine synapses in human brain samples from people who died with Alzheimerâ€™s disease and in models of disease. We are asking 3 main questions (1) Do amyloid and tau clump abnormally in synapses in human Alzheimerâ€™s disease brain where they may be working together to cause brain damage? (2) In a new mouse model of Alzheimerâ€™s can we better understand how amyloid beta and tau cooperate to damage synapses and can we recover brain function by lowering tau levels? (3) Can we use human stem cell derived neurons to learn more about how amyloid beta and tau work together to cause synapse loss? Together, these experiments are ground-breaking since they have the potential to further our understanding of how synapses are lost in Alzheimerâ€™s disease and to identify targets for effective therapeutic intervention, which is a critical unmet need in todayâ€™s health care system.
So far in the ALZSYN project, we have discovered that both amyloid beta and tau clump in synapses in the brains of people with Alzheimerâ€™s disease, but they are rarely found together. We see several different types of these proteins clumped in synapses. In our new mouse model, we discovered that amyloid beta and tau cooperate to cause a behavioural problem and changes in gene expression. These changes recover completely when tau levels are lowered. We are also treating mice with a drug to try and rescue synaptic damage.
The progress so far has resulted in 26 publications and appointment of Prof Spires-Jones to prestigious positions including the Scottish Science Advisory Council and the Chair of the grant review board at Alzheimerâ€™s Research UK.
During this project, Prof Spires-Jones and team have expanded our brain bank of human tissue prepared for array tomography and electron microscopy which is a unique resource. This has generated collaborations worldwide and led to 6 peer reviewed publications during the tenure of this grant. Future work on the project includes using human stem cell derived neurons to better understand these processes and test potential treatments. We have also registered novel stem cell lines in HSPCreg that have been generated from the well characterized ageing cohort the Lothian Birth Cohort 1936. A manuscript detailing these lines is in preparation.