Periodic Reporting for period 4 - Oligomers (Characterising protein oligomers and their role in neurodegenerative disease in humans)
Reporting period: 2020-03-01 to 2021-08-31
We have applied these method to induced pluripotent stem cell models of neurogenerative disease, clinical samples of cerebrospinal fluid and serum and post-mortem human brain. Our main findings are that aggregates of a range of sizes , 20-150 nm, are formed under normal conditions but there is a change in the size distribution and structure and composition of the aggregates during the development of neurodegenerative disease due to celllular stress, without changes in aggregate number. In particular, we find that the formation of long strings (protofilaments) of amyloid-beta occurs during the development of Alzheimer's disease which cause inflammation via a receptor called toll-like receptor 4. This makes toll-like receptor 4 a potential therapeutic tartget. We also found an increased proportion of a-synuclein aggregates in the serum of patients with Parkinson's disease making this a potential biomarker for disease detection. In the brain of Alzheimer's disease patients we detected inflammatory aggregates in all brain regions but found an increased proportion of smaller inflammatory aggregates in the regions where disease was starting to develop. This suggests the same process is occuring to a greater or lesser extent in different regions of the brain with the formation of more inflammatory aggregates in certain brain regions driving disease progression. We also showed that aggregate-induced inflammation caused long-term potentiation deficit in brain slices, a correlate of memory loss, linking aggregate induced inflammation to the cognitive decline observed in the disease process.
Overall, by exploiting our new methods we have found that small changes in aggregate size and shape occur during the development of Alzheimer's and Parkinson's disease leading to increased inflammation which drives further aggregation and spread of disease through the brain. Blocking inflammation may be a potential treatment and monitoring changes in aggregate size and composition has the potential for early disease diagnosis.
We have published 24 paper during the project describing these new methods and their application to disease models and human samples. We have also presented these results at international meetings on neurodegenerative disease.
Our results show that Toll-like receptor 4 is a potential therapeutic target for Alzheimer's and Parkinson's disease and more tractable than targeting the heterogeneous protein aggregates. We have also developed a potential biomarker for Parkinson's disease which may allow early disease detection and to monitor the efectiveness of potential therapies.