Researchers identified a biological signaling axis linking heart failure to synaptic loss and cognitive decline in male mice, according to a study published in Nature Communications. Cognitive impairment currently affects 30% to 80% of human heart failure patients, but the underlying mechanisms extending beyond reduced cerebral blood flow have remained poorly understood.
The researchers found that circulating factors released during heart failure induce senescence in brain blood-vessel endothelial cells. In tests using eight-month-old male mice subjected to transverse aortic constriction—a pressure-overload model—combined with plasma transfer, elevated levels of circulating TGFβ2 bound to the endothelial receptor TGFBR2. This interaction triggered the production and secretion of the protein SPARC via a non-canonical MEK/ERK–MYC molecular pathway.
Endothelial SPARC subsequently activates TLR4 receptors on microglia, the resident immune cells of the brain. That activation drives neuroinflammation and causes microglia to abnormally engulf synapses. Genetic deletion of endothelial Tgfbr2 or Sparc, as well as microglial deletion of Tlr4, prevented synapse loss and improved cognitive function in the mice. Pharmacological inhibition of TLR4 produced equivalent protective outcomes.
Mengdan Wang, Xiaoxuan Yu, Tursunjan Aziz, and Shiyao Zhang contributed equally as lead authors on the paper, which was accepted on Aug. 3, 2026, and published on Aug. 14, 2026. The research team included scientists from Xiamen University, Nanjing University of Chinese Medicine, and Tsinghua University. Grant support was provided by the National Natural Science Foundation of China, the Natural Science Foundation of Fujian Province, and the Natural Science Foundation of Xiamen.
