Cellular phasing could drive next-generation dementia therapies
Despite the known link between genetics and the development of Alzheimer’s disease, insights about its onset and progress remain limited. According to Bart De Strooper from KU Leuven in Belgium and the UK Dementia Research Institute, London, a key challenge is that many Alzheimer’s-associated genes are active in understudied microglia and astroglia cells. “Additionally, most experimental models can’t accurately reproduce important human features of the disease, with in vitro human cell systems too simplified and mouse models not comparable enough to humans,” adds De Strooper, coordinator of the CELLPHASE_AD project, which was funded by the European Research Council(opens in new window). To better address this gap in knowledge, CELLPHASE_AD studied human microglia, astrocyte and neuron activity in vivo – in a mouse model brain. “Our ‘village’ approach analysed multiple donor genotypes side-by-side under identical in vivo conditions, offering more robust results, with minimal animal experimentation,” notes De Strooper.
Linking genetics, cell states, pathology and therapeutic response
Cellular gene expressions change depending on the cell’s specific developmental phase, ultimately altering its function and behaviour. Suspecting that microglia(opens in new window) and astroglia(opens in new window) cells offer clues about Alzheimer’s onset and progress, CELLPHASE_AD wanted to characterise how these cells transition from stable (homeostatic) to diseased, tracked across the amyloid and tau pathology pathway strongly associated with Alzheimer’s. The team developed and studied mice genetically engineered to accept transplanted human microglia and to express amyloid plaques while ageing. “We showed that microglial roles are temporarily distinct. Interestingly, while early homeostatic states seem to contribute to seeding amyloid plaques, later states actually compact plaques limiting damage,” explains De Strooper. The team also demonstrated the importance of the APOE gene that encodes a protein involved in metabolising fats in astroglial cells – removal of the gene (in mice) also removing amyloid plaques. When human neurons were xenografted into mouse brains – laden with amyloid but not evidencing Alzheimer’s symptoms – the brain developed Alzheimer features, including tau pathology and selective neuronal loss. “This highlights a vulnerability to Alzheimer’s disease that may be human-specific,” says De Strooper. Studying this neuron loss revealed a pathway – a cell death programme associated with cognitive decline – as a potential target for new therapies. “We showed that amyloid clearance requires an intact part of an antibody known as the ‘Fc fragment’ alongside functional microglia revealing the importance of microglia for antibody efficacy,” remarks De Strooper. To reveal how both risk-related groups of genes, alongside specific genes, shape cell diseases and influence amyloid and tau pathology, the team generated and worked on large single cell and spatial genomic datasets. Analysis uncovered microglia and astrocyte gene networks working together to contain amyloid plaques, supporting the cellular phase of Alzheimer’s disease hypothesis.
Translating molecular insights into therapeutic strategies
In 2021, 57 million people were thought to have dementia worldwide(opens in new window), a figure increasing by around 10 million cases annually. Alzheimer’s disease is the most common form of dementia, equating to well over half of cases, with worldwide economic costs calculated at around USD 1.3 trillion. Reducing the suffering of individuals and families, alongside welfare costs, largely depends on developing effective treatments. CELLPHASE_AD’s insights into the biological links between genetic risk and causal pathways could improve patient stratification for smarter therapies. The models, capturing human cell behaviour in a brain, could also reduce drug discovery costs. Towards this end, a spin-out company was formed and is now part of Muna Therapeutics. Meanwhile, alongside peer-reviewed publications in ‘Cell’(opens in new window), ‘Science’(opens in new window), ‘Nature Neuroscience’(opens in new window) and ‘Nature Communications’(opens in new window) amongst others, the project’s methodologies, including validated xenograft protocols and computational pipelines, have already been shared and adopted by multiple laboratories.
