A team of researchers from the University of Medicine and Pharmacy of Craiova is making an important step in understanding how the brain can be helped to eliminate toxic substances that lead to the onset of Alzheimer’s disease (AD).

The study, published by the UMF Craiova team in the journal Alzheimer’s & Dementia, the official journal of the Alzheimer’s Association, shows that a protein called Aquaporin-4 (AQP4), responsible for water transport in the brain, also plays a key role in clearing soluble toxic amyloid fragments. These fragments precede the formation of insoluble amyloid plaques — one of the essential pathological hallmarks of the disease, closely associated with cognitive decline.

The researchers functionally tested two drugs — one that stimulates and one that inhibits AQP4 — on transgenic mice carrying human mutations that cause familial forms of AD. These mice spontaneously develop amyloid plaques. The results directly confirmed the bidirectional modulatory effect of AQP4 and its therapeutic potential:

• Treatment with the AQP4 facilitator led to a significant reduction in amyloid deposits in the animals’ brains, improved memory, and reduced anxiety, compared to both untreated transgenic mice and those treated with the AQP4 inhibitor.
• Treatment with the AQP4 inhibitor resulted in a massive increase in amyloid deposits, worsened memory deficits, and heightened anxiety, effectively accelerating the progression of the disease.

Photo caption: Treatment with the AQP4 facilitator leads to a significant reduction in both the number and size of amyloid plaques in the brains of treated animals, across all analyzed anatomical regions (middle column).

The discovery is significant because it confirms, in an animal model of Alzheimer’s disease (AD), the mechanism of action of AQP4 and opens a new direction for the development of treatments that help cerebral blood vessels eliminate toxins more efficiently. Its applicability extends not only to AD but also to other conditions associated with toxic accumulations in the brain, such as Parkinson’s disease and Huntington’s disease.

The neuropathological study was based on full-brain scanning of the analyzed animals, at resolutions that allowed for precise quantification of amyloid plaques—including their number, shape, and density—as well as blood vessel identification and the measurement of distances between plaques and the nearest surrounding blood vessels. Each of the analyzed images ranges in size between 2 and 5 GB, and the high level of detail extracted from such a large data volume was made possible by the use of a state-of-the-art confocal microscope, unique in the world, located at UMF Craiova. This technology allows researchers to observe tissue changes at the microscopic level, with details that go beyond the physical limitations imposed by the laws of light propagation (super-resolution microscopy).

The research team consists of specialists from Craiova, Cluj, and Belgium, coordinated by Dr. Daniel Pirici and Dr. Bogdan Cătălin, and is part of the PhD thesis of Dr. Marina Daniela Mănescu.

🔗Link to the article: https://doi.org/10.1002/alz.70164