NEURON AND MICROGLIA-SPECIFIC CHANGES IN SORL1-ASSOCIATED ALZHEIMER'S DISEASE IN THE HUMAN AND MOUSE BRAIN

Alzheimer's disease (AD) is a common progressive neurodegenerative disorder, yet its pathomechanism remains largely unclear. The role of microglia – the brain’s primary immune cells – in neurodegeneration and related inflammatory processes is emerging. Our study investigates disease-associated changes in microglia and neurons as well as cell-cell communication networks, particularly in the context of SORL1 (sortilin-related receptor) loss-of-function mutations that cause hereditary early-onset AD.
We performed single-cell RNA sequencing on human temporal cortex samples from controls and AD patients with or without SORL1 mutations. Data were analysed using the Seurat package, while cell-cell communication analysis was conducted with LIANA. In mice, we developed a CRISPR/Cas9 targeting strategy combined with in utero electroporation to achieve deletion of SORL1 in a subpopulation of cortical neurons in PSEN1//App_swe//tauP301L triple transgenic mice, an established AD model. Histological analyses were conducted using immunohistochemistry and confocal microscopy.
RNA profiling identified distinct human microglial and neuronal subtypes linked to both AD and SORL1 mutations, while the LIANA analysis revealed that cell-cell communication was severely impaired mostly in the case of microglia and OPC cells in patients with SORL1 mutations. In the AD mouse model, microglia interacting with SORL1-KO neurons showed morphological changes, and the microglia-neuron contact surface was also reduced.
Overall, our results indicate that molecular characteristics in patients with SORL1 loss-of-function mutations differ from Braak-matched AD cases and alterations involve microglial actions. Our study suggests that AD development could have several, presently unexplored links with microglia, warranting further research.