Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer’s mouse model

Abstract

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. Methods: To more fully elucidate neuroinflammatory changes associated with diabetes that may drive AD pathology, we combined the APP/PS1 mouse model with either high-fat diet (HFD, a model of pre-diabetes), the genetic db/db model of type 2 diabetes, or the streptozotocin (STZ) model of type 1 diabetes. We then used a multiplexed immunoassay to quantify cortical changes in cytokine proteins. 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.

Link between Diabetes and Alzheimer’s Disease Due to the Shared Amyloid Aggregation and Deposition Involving Both Neurodegenerative Changes and Neurovascular Damages

“…Some studies in older men have reported that men with the highest insulin levels, when performing the Mini-Mental State test, had 25% more errors compared to those with very low insulin levels [ 69 ]. The accumulation of amylin in the pancreas can decrease the level of insulin, which will lead to disruptions in carbohydrate metabolism (hyperglycemia) and will promote the development of neurodegenerative disorders [ 70 ]. The influence of high glucose levels on cognitive impairment was highlighted in the ACCORD-MIND study, which by assessing glycosylated hemoglobin (HbA1c) could detect the negative impact on cognitive tests [ 71 ].…”

“…To more fully clarify neuro-inflammatory alterations related with diabetes that could drive AD pathology, Sankar and co-workers [ 70 ] quantified cortical modifications in cytokine proteins in three different models of mice, with metabolic changes relevant to diabetes combined with a mouse model of AD (APP/PS1). Multiplexed immunoassay showed that pathology associated with either pre-diabetes, db/db, or streptozotocin models led to the upregulation of a comprehensive profile of cytokines, comprising chemokines (macrophage inflammatory protein-1 alpha, MIP−1α; monocyte chemoattractant protein-1, MCP−1; and macrophage inflammatory protein-1 beta, MIP−1β) and proinflammatory cytokines (IL−1α; interferon gamma, IFN-γ; and IL−3).…”

Alzheimer’s Disease and Diabetes: Role of Diet, Microbiota and Inflammation in Preclinical Models

“…Following this idea, neuroinflammation also plays a significant role in neurodegeneration [ 10 ]. In this sense, AD brains suffer neuroinflammatory changes including alterations in morphology and distribution of microglia and astrocytes, or increased expression of inflammatory mediators [ 11 , 12 , 13 ]. While microglia’s response to injury is typically beneficial, it can go awry in cases of chronic injury and long-term inflammation, such as in AD.…”

“…Besides, TNF-α contributes to impair insulin signalling by increasing insulin receptor substrate-1 phosphorylation [ 61 ]. Altogether, it seems that T2DM, or even prediabetes, can cooperatively modulate the expression of brain pro-inflammatory cytokines in AD [ 12 ], and both the prediabetic state and T2DM, promote microglia activation in AD mice [ 62 , 63 , 64 ], supporting the role of the inflammatory process as a link between AD and T2DM.…”

“…Increased neuroinflammation might not be exclusively related to HFD, since wildtype mice on HFD do not show a significant increase in the number of activated glial cells in the hippocampus, supporting a synergistic contribution when AD and metabolic disease are set together [ 240 ], as regularly observed in the clinic. MIP-1α, IL-1β, and IL-17 are altered in the cortex from APP/PS1 mice on HFD that also show increased IL-1β and TNF-α, accompanied by gliosis and disrupted neurogenesis in the hippocampus [ 12 , 240 ]. Higher levels of circulating blood monocytes, MCP-1, and ox-LDL are also observed in plasma from these mice, indicating severe systemic inflammation in these animals [ 238 ].…”