Drug target finding in Alzheimer’s disease
Alzheimer's disease, AD, is the most common form of dementia, affecting 4% of people of 60+ years, and its incidence increases to 15-25% between 80-89 years of age. In our aging population, AD is becoming more prevalent, and poses an enormous societal and economic burden. The brain of AD patients suffers from loss of nerve cells, the formation of amyloid beta (Abeta) protein deposits and abnormalities in the protein tau. Despite years of intense research, the cause of AD is still not known nor how the disease progresses. Moreover, no effective treatment is yet available. Novel targets for the development of new treatment strategies are urgently needed.
In recent years, the involvement of microglia, the local immune cells in the brain, in AD has become increasingly apparent. There are strong indications, also genetic (hereditary), that impaired activity of these cells possibly causes or exacerbates or the course of AD. The exact role and contribution of microglia on the development and course of AD is unknown and it the focus of this collaboration.
Hypothesis:
Abeta plaques and abnormalities in the tau protein have different effects on the brain. It was found that microglia respond differently to Abeta and tau. Whether these changes are good or bad for the brain is unknown. If it will become clear what the consequences of these microglia changes are, it will be possible to understand what is going wrong at a much earlier stage in the disease process.
Approach:
Our DNA contains genes, which carry information for proteins and determine the activity and function of a cell. The aim is to determine which genes change in AD for all cell types in the brain. They have already found changes caused by Abeta and tau, but what the consequences are is unknown.
By comparing individual brain cells of AD patients with the cells of unaffected people, they will reconstruct the sequence of changes in microglia, among other things, during the course of AD. The identification of microglia subtypes, which can be tissue-supporting or tissue-damaging on the other hand, offers opportunities for therapeutic strategies targeting harmful microglia.
Deliverables: They generated and optimised a protocol (Gerrits 2020) to determine the gene expression profiles of individual brain cells from AD patients, and determined how they were affected by amyloid and tau pathology (Alsema 2020; Gerrits, 2021).
The findings were reported in:
Gerrits et al., 2020, PMID 31846124
Alsema et al., 2020, PMID 33192286
Gerrits et al., 2021, PMID 33609158
