Impact of amyloid-β on microglia-mediated synaptic plasticity in the rodent and human cortex

Prof. Dr. Andreas Vlachos

• B14

Prof. Dr. Melanie Meyer-Lühmann

• B14

Project Summary

Microglia play a crucial role in modulating synaptic plasti city, acting as regulators of synaptic change and stability in the central nervous system. However, significant gaps in our understanding of synaptic plasticity-associated microglia persist, particularly regarding their transcriptional profiles, signaling pathways, dynamics, and their potential overlap with disease-associated microglia states. This knowledge gap is most evident in the adult human cortex, where insights into microglial contributions to synaptic plasticity remain limited. Our project aims to investigate microglial interactions with pyramidal neurons in both physiological and pathological conditions in mouse and human cortical tissue. We focus on the amyloid-β (Aβ) peptide and its impact on the spine apparatus organelle to unravel the signals and neuronal targets through which microglia affect synaptic plasticity. We aim to investigate and modulate microglial synaptic
functions across neurosurgical specimens (Aim 1 ), APP-transgenic mice, and Aβ seeding models (Aim 2 ). By integrating a spatially resolved framework that combines advanced electrophysiology, microscopy, and transcriptomic analyses (Aim 3), our objective is to delineate the transition of microglial functions from facilitating to impairing synaptic plasticity. Collaborating within the CRC/TRR, our goal is to achieve a substantial molecular understanding of synaptic plasticityassociated microglia and their link to Alzheimer’s disease (AD)-associated microglia states.