Tau, which normally stabilises neuronal structure, can misfold and form insoluble aggregates that spread through the brain in a characteristic pattern closely linked to disease progression. This process is often described as “prion-like,” as pathological tau can enter healthy cells and induce further misfolding.While tau propagation has traditionally been studied primarily in neurons, growing evidence suggests that other brain cells also play an active role.
In a recent study published in the Alzheimer´s & Dementia journal, researchers led by Maria Kreger Karabova focused on microglia – the brain’s resident immune cells responsible for monitoring the neural environment and clearing debris and pathogens.
The young researcher was recently awarded first place in the MED MUNI Internal grant agency Postdoc competition and received a two-year grant to support her future scientific performance in Dáša Bohačiakova´s research group at the Department of Histology and Embryology.
Microglia have long been viewed as protective cells that help remove toxic protein aggregates from the brain. However, most evidence for their role in tau pathology has come from mouse models, which do not fully reflect the biology of human microglia. To address this gap, the research team employed a human-induced pluripotent stem cell (hiPSC)-derived microglial model, enabling them to systematically investigate how human microglia interact with both normal (physiological) and pathogenic forms of tau.
A key methodological advance of the study is the development of an improved protocol for producing highly purified, endotoxin-free tau protein. This step was critical to ensure that the observed microglial responses were caused by tau itself rather than by contaminating inflammatory substances, an often-overlooked confounding factor in neurodegeneration research.
Using this refined experimental system, the researchers confirmed that microglia can efficiently take up both normal and pathogenic tau. Importantly, they uncovered a crucial difference in how these forms are processed. While physiological tau is effectively degraded, pathogenic tau resists complete breakdown. Instead, it is only partially processed, escapes the cell’s degradation machinery, and induces significant changes in microglial state. Strikingly, microglia were found to release this pathogenic tau back into the extracellular environment, including via extracellular vesicles, in a form that remains capable of spreading disease.
These findings challenge the prevailing assumption that enhancing microglial uptake of tau is inherently beneficial. On the contrary, the study suggests that tau uptake without efficient degradation may inadvertently contribute to AD progression by redistributing toxic protein species throughout the brain.
The research was the result of a highly collaborative and interdisciplinary effort. The hiPSC-derived microglial model was developed during Maria’s PhD at the James and Lillian Martin Centre for Stem Cell Research, Sir William Dunn School of Pathology, University of Oxford, under the supervision of William James and Sally Cowley. Collaborations with the University of Cambridge provided expertise in tau biochemistry and seeding competence, while multiple Oxford-based core facilities supported advanced imaging and proteomic analyses. The study also benefited from support by Alzheimer’s Research UK and industry collaboration.
By clarifying the dual role of microglia in AD, this work opens new therapeutic avenues. Rather than simply boosting microglial activity, future treatments may need to focus on maintaining microglia in a protective state that ensures toxic tau is fully degraded rather than redistributed. In the long term, such precision approaches could help slow or even prevent the progression of Alzheimer’s disease.
