Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer’s mouse model Sankar, Sitara B. Ramos Rodríguez, Juan José Pre-diabetes Type 1 diabetes (T1D) Type 2 diabetes (T2D) Cytokine profile Background: Diabetes is a risk factor for developing Alzheimer’s disease (AD); however, the mechanism by which diabetes can promote AD pathology remains unknown. Diabetes results in diverse molecular changes in the brain, including dysregulation of glucose metabolism and loss of cerebrovascular homeostasis. Although these changes have been associated with increased Aβ pathology and increased expression of glial activation markers in APPswe/ PS1dE9 (APP/PS1) mice, there has been limited characterization, to date, of the neuroinflammatory changes associated with diabetic conditions. Results: Our analysis revealed that pathology associated with either db/db, HFD, or STZ models yielded upregulation of a broad profile of cytokines, including chemokines (e.g., MIP-1α, MIP-1β, and MCP-1) and proinflammatory cytokines, including IL-1α, IFN-γ, and IL-3. Moreover, multivariate partial least squares regression analysis showed that combined diabetic-APP/PS1 models yielded cooperatively enhanced expression of the cytokine profile associated with each diabetic model alone. Finally, in APP/PS1xdb/db mice, we found that circulating levels of Aβ1-40, Aβ1-42, glucose, and insulin all correlated with cytokine expression in the brain, suggesting a strong relationship between peripheral changes and brain pathology. Conclusions: Altogether, our multiplexed analysis of cytokines shows that Alzheimer’s and diabetic pathologies cooperate to enhance profiles of cytokines reported to be involved in both diseases. Moreover, since many of the identified cytokines promote neuronal injury, Aβ and tau pathology, and breakdown of the blood-brain barrier, our data suggest that neuroinflammation may mediate the effects of diabetes on AD pathogenesis. Therefore, strategies targeting neuroinflammatory signaling, as well as metabolic control, may provide a promising strategy for intervening in the development of diabetes-associated AD. 2020-04-16T11:57:55Z 2020-04-16T11:57:55Z 2020 journal article Sankar, S. B., Infante-Garcia, C., Weinstock, L. D., Ramos-Rodriguez, J. J., Hierro-Bujalance, C., Fernandez-Ponce, C., ... & Garcia-Alloza, M. (2020). Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer’s mouse model. Journal of neuroinflammation, 17(1), 1-15. http://hdl.handle.net/10481/61302 10.1186/s12974-020-1707-x eng http://creativecommons.org/licenses/by/3.0/es/ open access Atribución 3.0 España Springer Nature