Early minor stimulation of microglial TLR2 and TLR4 receptors attenuates Alzheimer's disease–related cognitive deficit in rats: behavioral, molecular, and electrophysiological evidence

Pourbadie, Hamid Gholami; Sayyah, Mohammad; Khoshkholgh-Sima, Baharak; Choopani, Samira; Nategh, Mohsen; Motamedi, Fereshteh; Shokrgozar, Mohammad Ali

doi:10.1016/j.neurobiolaging.2018.06.020

Cited by 58 publications

(51 citation statements)

References 92 publications

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“…The role TLR4 plays in AD is not fully deciphered; a recent report found the minor allele of the rs4986790 polymorphism (G) of TLR4 to be associated with a reduced risk of developing AD and higher cortical thickness in human patients [14]. Low-dose ligands for TLR2 and TLR4 attenuated learning deficits in rats when administered before intracerebroventricular injection of Amyloid β (Aβ) peptides [15]. This was consistent with findings from Tau-transgenic AD model mice [16].…”

Section: Introductionsupporting

confidence: 72%

Dietary Wheat Amylase Trypsin Inhibitors Impact Alzheimer’s Disease Pathology in 5xFAD Model Mice

Guilherme

Zevallos

Pesi

et al. 2020

IJMS

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Wheat amylase trypsin inhibitors (ATIs) represent a common dietary protein component of gluten-containing cereals (wheat, rye, and barley). They act as toll-like receptor 4 ligands, and are largely resistant to intestinal proteases, eliciting a mild inflammatory response within the intestine after oral ingestion. Importantly, nutritional ATIs exacerbated inflammatory bowel disease and features of fatty liver disease and the metabolic syndrome in mice. For Alzheimer’s disease (AD), both inflammation and altered insulin resistance are major contributing factors, impacting onset as well as progression of this devastating brain disorder in patients. In this study, we evaluated the impact of dietary ATIs on a well-known rodent model of AD (5xFAD). We assessed metabolic, behavioral, inflammatory, and microbial changes in mice consuming different dietary regimes with and without ATIs, consumed ad libitum for eight weeks. We demonstrate that ATIs, with or without a gluten matrix, had an impact on the metabolism and gut microbiota of 5xFAD mice, aggravating pathological hallmarks of AD. If these findings can be translated to patients, an ATI-depleted diet might offer an alternative therapeutic option for AD and warrants clinical intervention studies.

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Section: Introductionsupporting

confidence: 72%

Dietary Wheat Amylase Trypsin Inhibitors Impact Alzheimer’s Disease Pathology in 5xFAD Model Mice

Guilherme

Zevallos

Pesi

et al. 2020

IJMS

View full text Add to dashboard Cite

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“…Oral administration of LPS to mice could activate peritoneal macrophages [287] and enhance the phagocytic activity of Aβ 1-42 by primary microglia via the TLR4 pathway [288]. Studies using low doses of either MPL or TLR2 agonist-Pam3Cys administered intracerebroventricularly to rats treated with Aβ 1-42 improved their memory function; restored the impaired long-term potentiation induced by Aβ; decreased TNF-α and Aβ deposits, enhanced expression of microglial marker, arginase 1, and increased polarization of hippocampal microglia to an anti-inflammatory phenotype [289].…”

Section: Lipid Amentioning

confidence: 99%

Lipids and Alzheimer’s Disease

Kao

et al. 2020

IJMS

342

263

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Lipids, as the basic component of cell membranes, play an important role in human health as well as brain function. The brain is highly enriched in lipids, and disruption of lipid homeostasis is related to neurologic disorders as well as neurodegenerative diseases such as Alzheimer’s disease (AD). Aging is associated with changes in lipid composition. Alterations of fatty acids at the level of lipid rafts and cerebral lipid peroxidation were found in the early stage of AD. Genetic and environmental factors such as apolipoprotein and lipid transporter carrying status and dietary lipid content are associated with AD. Insight into the connection between lipids and AD is crucial to unraveling the metabolic aspects of this puzzling disease. Recent advances in lipid analytical methodology have led us to gain an in-depth understanding on lipids. As a result, lipidomics have becoming a hot topic of investigation in AD, in order to find biomarkers for disease prediction, diagnosis, and prevention, with the ultimate goal of discovering novel therapeutics.

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“…A wide range of therapeutic compounds (Table 3) have demonstrated their efficacy in animal models of AD-like pathologies, mainly by inhibiting TLR4 expression, suppressing microglial activation and pro-inflammatory cytokine levels, ameliorating learning and memory functions, inhibiting oxidative stress, and reducing apoptotic cell death and Aβ load (number and size of Aβ deposit) [120][121][122][123][124][125][126].…”

Section: Effects Of Tlr4 Blockade In Admentioning

confidence: 99%

Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting

Paudel

Angelopoulou

Piperi

et al. 2020

Cells

179

128

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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and a leading cause of dementia, with accumulation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs) as defining pathological features. AD presents a serious global health concern with no cure to date, reflecting the complexity of its pathogenesis. Recent evidence indicates that neuroinflammation serves as the link between amyloid deposition, Tau pathology, and neurodegeneration. The high mobility group box 1 (HMGB1) protein, an initiator and activator of neuroinflammatory responses, has been involved in the pathogenesis of neurodegenerative diseases, including AD. HMGB1 is a typical damage-associated molecular pattern (DAMP) protein that exerts its biological activity mainly through binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). RAGE and TLR4 are key components of the innate immune system that both bind to HMGB1. Targeting of HMGB1, RAGE, and TLR4 in experimental AD models has demonstrated beneficial effects in halting AD progression by suppressing neuroinflammation, reducing Aβ load and production, improving spatial learning, and inhibiting microglial stimulation. Herein, we discuss the contribution of HMGB1 and its receptor signaling in neuroinflammation and AD pathogenesis, providing evidence of its beneficial effects upon therapeutic targeting.

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Early minor stimulation of microglial TLR2 and TLR4 receptors attenuates Alzheimer's disease–related cognitive deficit in rats: behavioral, molecular, and electrophysiological evidence

Cited by 58 publications

References 92 publications

Dietary Wheat Amylase Trypsin Inhibitors Impact Alzheimer’s Disease Pathology in 5xFAD Model Mice

Dietary Wheat Amylase Trypsin Inhibitors Impact Alzheimer’s Disease Pathology in 5xFAD Model Mice

Lipids and Alzheimer’s Disease

Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting

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