Effects of Distinct n-6 to n-3 Polyunsaturated Fatty Acid Rations on Insulin Resistant and AD-like Phenotypes in High-Fat Diets-Fed APP/PS1 Transgenic Mice

Abstract

Background: Type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) are two prevalent diseases with comparable pathophysiological features and genetic predisposition. Polyunsaturated fatty acids (PUFAs) are essential in maintaining normal brain function. However, little is known about the impact of dietary n-6/n-3 PUFA ratio on AD-like pathology, especially in high-fat diet (HFD)-fed AD model mice. Methods: In the present study, the APP/PS1 mice were treated with 60% HFD for 3.5 months to induced insulin resistance. After that, 45% HFD with different n-6/n-3 PUFA ratios (n-6/n-3=1:1, 5:1 or 16:1) was applied for additional 3.5 months treatment. Following the dietary intervention, the behavior of mice was observed using the Water maze. Following behavioral testing, the animals were euthanized, and serum and tissue samples were collected for biochemical, histological and pathological analyses and evaluation. Cortical fatty acid profile was measured by gas chromatography. Western Blot and immunohistochemistry methods were used to detect protein expression of molecules related to AD pathology and insulin signaling pathway(s) in the brain sample tissues. Immunofluorescence assay was used to uncover the expression and migration of NF-κB in the cortex. qPCR method was applied to determine the gene expression of cortical pro-inflammatory cytokines.Results: HFD caused insulin resistance, increased serum IL-6 and TNF-α level, elevated cortical soluble Aβ1-40, Aβ1-42 content, and increased brain n-6/n-3 PUFAs ratio in APP/PS1 mice. Increased APP and BACE1 protein expression and p-IR/IR ratio, but decreased pro-inflammatory cytokines mRNA expression was observed in the cortex from 60% HFD-fed APP/PS1 mice. N-3 PUFAs rich diet (n-6/n-3=1:1) relieved insulin resistance and hyperlipidemia induced by 60% HFD. Cortical soluble Aβ1-40 and Aβ1-42 contents, the expression of cortical APP, GLUT3, insulin metabolism related molecules, and NF-κB pathway downstream pro-inflammatory cytokines showed a dietary n-6/n-3 PUFAs ratio-dependent way, indicating that dietary n-6/n-3 PUFA ratio plays a critical role in modifying the responses of serum inflammatory cytokine, AD pathology, cortical n-6/n-3 PUFAs ratio, insulin signaling and neuroinflammation to HFD treatment.Conclusion: Dietary n-6/n-3 PUFA ratio play an important role in modifying AD pathophysiology, insulin signaling pathway, and neuro-inflammation response to high fat diet treatment in brain.