Scientists led by Dr Claire Durrant (UK DRI at Edinburgh) have used living human brain tissue to show for the first time how a toxic form of a protein linked to Alzheimer’s can stick to and damage synapses, the connections between brain cells.

An international research team led by Professor Kiavash Movahedi from the Brussels Center for Immunology at the Vrije Universiteit Brussel has published unexpected results in the journal Immunity. Their study sheds new light on the possibility of effectively replacing defective microglia—the brain’s immune cells—marking a potential breakthrough in the treatment of neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

Microglia are essential for healthy brain function. Defective microglia are increasingly linked to the development of neurodegenerative disorders.

“Microglia are unique,” says Prof. Movahedi. “They originate early in embryonic development and maintain themselves throughout life without being replaced by new cells from the blood. That makes them special, but also vulnerable.”

The Hopf whole-brain model, based on structural connectivity, overcomes limitations of traditional structural or functional connectivity-focused methods by incorporating heterogeneity parameters, quantifying dynamic brain characteristics in healthy and diseased states. Traditional parameter fitting techniques lack precision, restricting broader use. To address this, we validated parameter fitting methods using simulated networks and synthetic models, introducing improvements such as individual-specific initialization and optimized gradient descent, which reduced individual data loss. We also developed an approximate loss function and gradient adjustment mechanism, enhancing parameter fitting accuracy and stability.

Understanding synapse loss in Alzheimer’s disease has been hampered by a lack of human model systems. Here, the authors show that manipulation of physiological or pathological Aβ has differing effects on synapses in live human brain slice cultures.