New approaches to find early microglia targets to alter inflammation and depression in Alzheimer’s disease

We will study the interaction of microglia with Aβ aggregation in Alzheimer’s disease (AD) and it role in depression. Recent GWAS have identified the largest genetic risk factors for AD to be related to innate immunity and microglia.

Especially genes related to receptors important in microglial sensing of aggregated Aβ. The overrepresented incident of depression in patients with mild cognitive impairment is suggested to be an early sign of AD. To study the first aggregation in AD brain tissue we will use high-resolution synchrotron-based FTIR spectromicroscopy (MAX IV Lab) that can detect the very first Aβ aggregates. This technology will be used to study the first activation of microglial cells. The microglia phenotype sensing the first aggregates of Aβ will be studied by immuno, laser dissection microscopy and the new 2D RNAseq technology Spatial Transcriptomics to identify the gene profile in microglia related to their association to Aβ plaque in brain sections. We have already identified a microglia target, galectin-3, that is expressed specifically in microglia that are in association with Aβ plaque. Galectin-3 will further be studied (inhibitors, KO studies) to elucidate the mechanisms involved and its therapeutic potential. Last, we will use a mouse model to induce depression (maternal separation) in AD mice and by using the approaches mentioned above we will identify early microglial alteration that can lead to depression in adulthood.