The Role of Microglia in Alzheimer´s Disease

• Applicant: Dr. Emile Wogram
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 393821200

Alzheimer´s disease (AD) is the most prevalent age-related neurodegenerative disorder and most common cause of dementia. About 5.3 million Americans are diagnosed with AD or ~1 in 8 people older than 65 years. Yet, no effective treatment is available and the illness culminates in death.The vast majority of patients suffer from the sporadic form of AD with multiple risk factors contributing to the disease. Recently, genome wide association studies of patients with sporadic AD have revealed a plethora of genetic variants associated with the disease. Remarkably, the highest association was described for genes such as TREM2, CD33 and ApoE that are highly expressed by the immune competent cells of the brain, called microglia. This suggests significant participation of microglia in sporadic AD. In accordance with this notion, many other studies have revealed the important role of microglia in AD.The aim of this project is to establish a complex 3D system to investigate the role of human microglia in sporadic AD. By combining genome-editing techniques with stem cell technologies, human microglia will be generated that differ exclusively at single AD-associated genetic variants. These cells are further integrated in mouse brain slices that lack endogenous microglia. This 3D AD-model system allows long-term investigations of the phenotype and non-autonomous functions of human microglia in an in vitro system supporting all types of neurons and glia in an anatomically preserved environment.Various sensitive techniques will be utilized to characterize microglial phenotypes and accumulating pathological changes in the brain tissue. As the genetically modified human microglia differ only at known gene loci, subtle AD-related pathological changes can be linked to specific microglial genes.The ultimate goal of this project is to understand complex microglia–neuron interactions in the pathogenesis of AD and to devising innovative therapeutic strategies using immune modulations to alter the activated phenotype of microglia and improve neuronal survival in AD patients.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Rudolf Jaenisch