Microglia as drug targets in Alzheimer’s disease
Alzheimer's disease, AD, is the most common form of dementia, affecting 4% of people at the age 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. People with AD progressively suffer from forgetfulness, disorientation, language problems, loss of motivation, mood swings and cognitive decline.
In the brains of AD patients excessive loss of nerve cells is obsered, together with 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 of the brain, in AD has become increasingly apparent. There is strong evidence, also genetic (hereditary), that impaired functions of these cells likely causes or worsens the course of AD. The exact role and contribution of microglia on the development and course of AD is unknown and the focus of this collaboration.
Hypothesis:
Abeta plaques and abnormalities in the tau protein have different effects on the brain. It was reported that microglia respond differently to Abeta and tau. Whether these changes are good or bad for the brain is unknown. It is hypothesized that Abeta-associated microglia are tissue-damaging and tau-associated microglia are tissue protective cells. If it becomes understandable how the functional properties of these microglia subsets, it might be possible to determine which processes drive AD progression and possibly even identify the processes that are perturbed at an early stage in the disease process.
Approach:
Our DNA contains genes, which carry information for proteins and determine the activity and function of a cell. By comparing individual brain cells of AD patients with the cells of unaffected people, they have reconstructed the sequence of changes in microglia during the course of AD (Gerrits et al., 2020 & 2021; Alsema et al., 2020). The identification of microglia subtypes, which can be tissue-supporting or tissue-damaging, offers opportunities for therapeutic strategies targeting harmful microglia.
Deliverables: aim to determine the exact localisation and (altered) functions of microglia subsets identified in Alzheimer’s dementia in relation to amyloid and tau pathology.
The findings were reported in:
Gerrits et al., 2020, PMID 31846124
Alsema et al., 2020, PMID 33192286
Gerrits et al., 2021, PMID 3360915