Accumulation of amyloid in breast cancer is a well‐known phenomenon, but only immunoglobulin light‐chain amyloidosis (AL) or transthyretin (TTR) amyloid had been detected in human breast tumor samples previously. We recently reported that another amyloidogenic peptide, amyloid beta (Aβ), is present in an aggregated form in animal and human high‐grade gliomas and suggested that it originates systemically from the blood, possibly generated by platelets. To study whether breast cancers are also associated with these Aβ peptides and in what form, we used a nude mouse model inoculated with triple‐negative inflammatory breast cancer cell (SUM‐149) xenografts, which develop noticeable tumors. Immunostaining with two types of specific antibodies for Aβ identified the clear presence of Aβ peptides associated with (a) carcinoma cells and (b) extracellular aggregated amyloid (also revealed by Congo red and thioflavin S staining). Aβ peptides, in both cells and in aggregated amyloid, were distributed in clear gradients, with maximum levels near blood vessels. We detected significant presence of amyloid precursor protein (APP) in the walls of blood vessels of tumor samples, as well as in carcinoma cells. Finally, we used ELISA to confirm the presence of elevated levels of mouse‐generated Aβ40 in tumors. We conclude that Aβ in inflammatory breast cancer tumors, at least in a mouse model, is always present and is concentrated near blood vessels. We also discuss here the possible pathways of Aβ accumulation in tumors and whether this phenomenon could represent the specific signature of high‐grade cancers.

Background/Objectives: Diabetes mellitus is a metabolic disorder, and hyperglycemia results in abnormal brain function. Since glycolysis is the main energy pathway in glial cells, astrocytes possess a more developed glyoxalase (Glo) system than neurons and exhibit better survival. Glycolysis helps to protect glia from (i) dicarbonyl stress and (ii) formation of advanced glycation end products (AGEs). Since aminoguanidine (AG) is an inhibitor of AGE production, the purpose of this study was to determine the role of AG in crucial astrocytic proteins, such as Kir4.1, Glo1, and Glo2, in hyperglycemic conditions. Methods: We cultured astrocytes in normal (5 mM)- and high (25 mM)-glucose conditions. After two weeks, we seeded the cells in six-well plates, with 300,000 cells/well, and then treated them with 9 mM of AG for 24 h. Results: Expression of the glyoxalases Glo1 and Glo2, and of Kir4.1, is decreased in hyperglycemic conditions; however, treatment with AG recovers the expression of the Kir4.1 protein as well as the inward currents of hyperglycemic astrocytes. Conclusion: We demonstrated that regulation of the glyoxalase system via AG or another scavenger of carbonyl and aldehydes containing polyamine groups can contribute to the recovery of astrocyte function in diabetic patients.

Hyperglycemia is linked to a higher risk of diabetes, epilepsy, and seizures, which contribute to increased mortality. Previous research has shown that hyperglycemia impairs the function of the polyamine-dependent Kir4.1 channels in cultured astrocytes, and a similar effect was observed in male astrocytes from diabetic (db/db) mice. However, whether there are sex differences in this effect remains unclear. This study aims to compare Kir4.1 channel function in 10–12 week old brains of female db/db mice with that in males and non-diabetic heterozygous (db/+). We performed mRNA analyses, Western blotting (WB), glucose level measurements, and patch-clamp recordings from hippocampal astrocytes in brain slices to assess Kir4.1 channel activity in db/db and db/+ mice of both sexes. Our results showed increased glucose levels in diabetic db/db mice, especially in males, along with (1) reduced synthesis of Kir4.1 channel protein, (2) reduced membrane potential, (3) decreased Kir currents, and (4) compromised potassium uptake. Female diabetic astrocytes exhibited significantly lower barium-blocked Kir4.1 currents compared to diabetic males. Additionally, barium-insensitive currents (leakage currents) were upregulated in db/db mice, likely as a compensatory response to hyperglycemia. In conclusion, diabetes impairs astrocyte function by downregulating Kir4.1 channels, with a more pronounced effect in male diabetic mice. This impairment may increase seizure risk by affecting the ability of astrocytes to maintain extracellular ion balance.