Justyna Marta Domańska

Background: The western diet (WD), characterized by a combination of simple carbohydrates, saturated fatty acids and cholesterol, is known to induce metabolic syndrome and systemic inflammation. These peripheral disorders induce neuroinflammation and affect brain function, suggesting that WD may have a significant impact on Alzheimer’s disease (AD) progression (Więckowska‐Gacek et al., 2021). In this study we aimed to verify the hypothesis that WD feeding accelerates neuroinflammation, resulting in accelerated deposition of Aβ plaques, accelerated appearance of neurodegeneration markers and destabilization of neuronal cytoskeleton.Methods: Transgenic male mice expressing human APP with the Swedish mutation (APPswe) were divided into three age groups: 4‐ and 8‐month old animals (4M, 8M) represent early pre‐symptomatic stages of AD, while 12‐month old animals (12M) represent later stages of AD with visible amyloid pathology. The APPswe mice were fed standard or western diet from the 3rd month of age. The effect of WD on selected markers was analyzed in the hippocampus and entorhinal cortex by Western blotting and immunohistochemistry.Results: Compared to control mice fed standard diet, WD feeding induced astrogliosis (GFAP) in the hippocampus as early as in 4M, followed by several changes in 8M such as activation of the pro‐inflammatory microglia (↑Iba1, ↓CD68, ↓P2RY12), a decrease in the level of TLR4, and the fluctuations of levels of pro‐inflammatory cytokines (IL‐1β, IL‐6). These changes in the hippocampus at 8M co‐occurred with enhanced production of Aβ plaques. Moreover, WD accelerated the processes associated with age‐related neurodegeneration (lower levels of PSD95 in 8M, and of NeuN in 12M). In the entorhinal cortex, the examined molecular changes appeared with a delay in time or not at all.Conclusion: These results indicate that the westernized pattern of nourishment is an important modifiable risk factor of AD which can accelerate development of AD pathology. Furthermore, the data demonstrate that, compared to the entorhinal cortex, the hippocampus is a brain structure that is generally more sensitive to the macronutrient composition characteristic of WD, manifested by accelerated neuroinflammation, amyloidopathy and neurodegeneration.Polish National Science Center grants: 2018/29/N/NZ7/01724, 2014/15/D/NZ4/04361

Background: One of the hypotheses for the ethiology of sporadic Alzheimer’s disease (AD) focuses on systemic inflammation as a driving force of aging. Another known risk factor of AD is obesity and insulin resistance, known to be associated with the activation of pro‐inflammatory cytokines.The aim of this study was to verify the hypothesis that systemic inflammation induced by lipopolysaccharides (LPS) of Gram‐negative bacteria may disrupt insulin signaling in the brain, leading to the development of neuropathological changes typical of AD. We tested this hypothesis in wild type mice by examining the LPS effect on the initiation and propagation of major neuropathological features of AD, such as amyloid‐β (Aβ) and hyperphosphorylated tau protein (p‐tau) pathologies that start from the entorhinal cortex and progresses to the hippocampus.Method: 3‐months old male C57BL/6J mice were injected with LPS (0.5 mg/kg) for 3 days. Mice were then analyzed at 4, 8, 12 and 16 months of age for brain markers of: insulin resistance (p‐IRS‐1(Ser616)), p‐tau pathology (p‐tau (Thr231)) and amyloid pathology (APP levels) in the entorhinal cortex and hippocampus.Result: The results revealed an increase in p‐IRS levels from 4 months of age in both brain structures. In the entorhinal cortex an increase in p‐tau levels was observed in 8‐month‐old mice with no change in APP levels. Conversely, in the hippocampus, a decrease in levels of the full form of APP was observed in the 16‐month‐old group, with no change in p‐tau levels.Conclusion: LPS, as an infectious, pro‐inflammatory agent, leads to the development of AD neuropathology. In the absence of genetic alterations typical of AD, LPS induces insulin resistance in the brain, and then leads to an increase in tau phosphorylation in the entorhinal cortex in the early stage of the disease progression, followed by the amyloidopathy in the hippocampus, with a significant delay.National Science Centre, Poland: UMO‐2014/15/D/NZ4/04361.

Background: Western diet (WD) is a type of nourishment based on ultra‐processed foods, rich in simple sugars and saturated fats. Long‐term consumption of WD may lead to disruption of insulin signaling and development of insulin resistance. It is supposed that insulin resistance is a probable risk factors for Alzheimer’s disease (AD). The aim of this study was to verify this hypothesis in wild type mice by checking the WD effect on initiation and propagation of main neuropathological AD features such as amyloid‐β (Aβ) plaques and neurofibrillary tangles, which start from the entorhinal cortex in the temporal area, and progresses to the hippocampus, resulting in the loss of memory and cognition.Method: Males of wild type C57BL/6J mice were fed WD diet or standard diet (SD; CTR). Mice experimental groups (WD and CTR) were divided into age subgroups 4‐, 8‐, 12‐ and 16‐month‐old. In the first step, the WD‐diet dependent insulin signaling was analyzed, and the levels of the insulin pathway components: p‐IRS‐1(Ser616), p‐Akt(473), p‐GSK‐3β(Ser9) in the entorhinal cortex and hippocampus were assessed. To analyze further whether WD‐derived impairments in insulin signaling may induce neuropathological AD features, p‐Tau(Thr231) and APP/Aβ were analyzed by immunoblotting and immunofluorescence of mouse brain tissue sections from entorhinal cortex and the hippocampus.Result: Entorhinal cortex proved to be more sensitive to WD‐dependent insulin impairments than the hippocampus: immunoblotting analysis of mouse entorhinal cortex brain lysates revealed an increase in p‐IRS‐1(Ser616) levels, indicating the development of insulin resistance under WD diet. Moreover, a change in the localization of p‐Tau(Thr231) in cellular compartments from fibers to nerve cell bodies indicated a progressive tauopathy. In addition, we also observed an age‐dependent decrease in APP protein levels correlating with the appearance of Aβ peptides in the cytoplasm of neurons under the WD diet.Conclusion: Obtained results suggest that the WD diet, by inducing abnormalities in insulin signaling in the brain, promotes the development of AD, and may be consider as a significant modifiable risk factor for AD, additional to the genetic risk factors.