Older plaques show stronger association with damage to brain nerve cell connections

Plaques made up of the protein amyloid beta are one of the most recognized pathological hallmarks in the brain of Alzheimer’s disease patients. However, why some plaques appear more harmful than others has long been unclear. Researchers led by Jörg Hanrieder, professor of neurochemistry at the Sahlgrenska Academy, University of Gothenburg now show that plaques are not static – they mature and evolve over time, and the most mature plaques have the strongest effect on the brain’s neural connections.

“We see that older plaques are denser, more fibrillar, and clearly associated with greater synapse loss. This shows that the age of a plaque is a key factor in how damaging it becomes,” says Jörg Hanrieder.

Different stages

The results are published in Nature Communications. The study is based on a method developed by the researchers that makes it possible to “timestamp” plaques in the brains of mice with Alzheimer-like changes. By combining mass spectrometry based chemical imaging with so-called spatial biology, they were able to follow how each plaque forms, grows, and affects nearby nerve cells. Spatial biology makes it possible to analyze molecules directly in tissue and to link changes in cell states to the development of the surrounding tissue.

The results show that it is not only the amount of plaque that determines how the disease progresses, but also how the plaques mature and change. This knowledge could contribute to improved diagnostics and more precisely targeted treatments that slow disease progression before large portions of the brain’s neural connections are lost.

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“If we can identify which plaques are most harmful and at what stage they are, future drugs can be designed to target the most destructive forms of amyloid,” says Jörg Hanrieder.

Laboratory for spatial biology

The research behind the study has also led to the establishment of a new laboratory for spatial biology at the Sahlgrenska Academy. Homepage: https://www.gu.se/en/neuroscience-physiology/spatial-biology

This initiative, driven by the researchers themselves, aims to make this rapidly growing technology accessible to more users. The development is expected to have major significance for research on the interaction between cells and tissues in the coming decades. 

Article: Isotope-encoded spatial biology identifies plaque-age-dependent maturation and synaptic loss in an Alzheimer’s disease mouse model.
DOI: https://doi.org/10.1038/s41467-025-63328-y