Advanced glycation endproducts and their receptor RAGE in Alzheimer's disease.
TL;DR: In this paper, the authors revisited the hypothesis that advanced glycation endproducts (AGEs) and their receptor RAGE may play an important role in disease pathogenesis by influencing transport of β-amyloid into the brain or by manipulating inflammatory mechanisms.
About: This article is published in Neurobiology of Aging.The article was published on 2011-05-01. It has received 444 citations till now. The article focuses on the topics: RAGE (receptor) & Senile plaques.
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TL;DR: There is evidence for a remarkable convergence in the mechanisms responsible for the sensing, transduction, and amplification of inflammatory processes that result in the production of neurotoxic mediators in neurodegenerative diseases.
2,838 citations
TL;DR: Investigative and drug development efforts should be diversified to fully address the multifactoriality of Alzheimer's disease.
1,558 citations
TL;DR: The impact of innate and adaptive immune responses on the central nervous system in autoimmune, viral and other neurodegenerative disorders, and their contribution to either damage or repair is reviewed.
Abstract: Neurodegeneration, the slow and progressive dysfunction and loss of neurons and axons in the central nervous system, is the primary pathological feature of acute and chronic neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, neurotropic viral infections, stroke, paraneoplastic disorders, traumatic brain injury and multiple sclerosis. Despite different triggering events, a common feature is chronic immune activation, in particular of microglia, the resident macrophages of the central nervous system. Apart from the pathogenic role of immune responses, emerging evidence indicates that immune responses are also critical for neuroregeneration. Here, we review the impact of innate and adaptive immune responses on the central nervous system in autoimmune, viral and other neurodegenerative disorders, and discuss their contribution to either damage or repair. We also discuss potential therapies aimed at the immune responses within the central nervous system. A better understanding of the interaction between the immune and nervous systems will be crucial to either target pathogenic responses, or augment the beneficial effects of immune responses as a strategy to intervene in chronic neurodegenerative diseases.
1,133 citations
TL;DR: The role of the HMGB1-RAGE axis in inflammation and cancer is reviewed, which has been implicated in sterile inflammation as well as in cancer, diabetes, and Alzheimer's disease.
Abstract: The immune system has evolved to respond not only to pathogens, but also to signals released from dying cells. Cell death through necrosis induces inflammation, whereas apoptotic cell death provides an important signal for tolerance induction. High mobility group box 1 (HMGB1) is a DNA-binding nuclear protein, released actively following cytokine stimulation as well as passively during cell death; it is the prototypic damage-associated molecular pattern (DAMP) molecule and has been implicated in several inflammatory disorders. HMGB1 can associate with other molecules, including TLR ligands and cytokines, and activates cells through the differential engagement of multiple surface receptors including TLR2, TLR4, and RAGE. RAGE is a multiligand receptor that binds structurally diverse molecules, including not only HMGB1, but also S100 family members and amyloid-β. RAGE activation has been implicated in sterile inflammation as well as in cancer, diabetes, and Alzheimer's disease. While HMGB1 through interacti...
1,126 citations
TL;DR: Molecular mechanisms that link obesity, diabetes and AD, including oxidative stress, mitochondrial dysfunction, and inflammation that are observed in these disorders are discussed.
422 citations
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TL;DR: These features of HMGB1 are discussed and recent advances that have led to the preclinical development of therapeutics that modulateHMGB1 release and activity are summarized.
Abstract: High-mobility group box 1 protein (HMGB1), which previously was thought to function only as a nuclear factor that enhances transcription, was recently discovered to be a crucial cytokine that mediates the response to infection, injury and inflammation. These observations have led to the emergence of a new field in immunology that is focused on understanding the mechanisms of HMGB1 release, its biological activities and its pathological effects in sepsis, arthritis, cancer and other diseases. Here, we discuss these features of HMGB1 and summarize recent advances that have led to the preclinical development of therapeutics that modulate HMGB1 release and activity.
2,318 citations
TL;DR: The cytotoxic action of A beta on neurons results from free radical damage to susceptible cells, suggesting that A beta activates a member of this class of enzymes.
2,060 citations
TL;DR: Concentrations of copper (Cu), iron (Fe) and zinc (Zn) were measured in the rims and cores of senile plaques (SP) and in the neuropil of the amygdala of nine Alzheimer's disease patients and in that of five neurologically normal control subjects using micro particle-induced X-ray emission (micro-PIXE).
1,963 citations
TL;DR: The diabetes attributable risk for dementia of 8.8% suggests that diabetes may have contributed to the clinical syndrome in a substantial proportion of all dementia patients.
Abstract: Objective: To determine the influence of type 2 diabetes mellitus on the risk of dementia and AD. Background: Both dementia and diabetes are frequent disorders in elderly people. Methods: Prospective population-based cohort study among 6,370 elderly subjects. At baseline study participants were examined for presence of diabetes mellitus. Nondemented participants were followed up, on average, for 2.1 years. Incident dementia was diagnosed using a three-step screening and comprehensive diagnostic workup. To complete the follow-up, medical files were studied of persons who could not be reexamined. We estimated relative risks with proportional hazard regression, adjusting for age, sex, and possible confounders. Results: During the follow-up, 126 patients became demented, of whom 89 had AD. Diabetes mellitus almost doubled the risk of dementia (relative risk [RR] 1.9 [1.3 to 2.8]) and AD (RR 1.9 [1.2 to 3.1]). Patients treated with insulin were at highest risk of dementia (RR 4.3 [1.7 to 10.5]). Conclusion: The diabetes attributable risk for dementia of 8.8% suggests that diabetes may have contributed to the clinical syndrome in a substantial proportion of all dementia patients.
1,949 citations
TL;DR: Evidence is presented that the 'receptor for advanced glycation end products' (RAGE) is such a receptor, and that it mediates effects of the peptide on neurons and microglia and indicates that it is relevant to the pathogenesis of neuronal dysfunction and death.
Abstract: Amyloid-beta peptide is central to the pathology of Alzheimer's disease, because it is neurotoxic--directly by inducing oxidant stress, and indirectly by activating microglia. A specific cell-surface acceptor site that could focus its effects on target cells has been postulated but not identified. Here we present evidence that the 'receptor for advanced glycation end products' (RAGE) is such a receptor, and that it mediates effects of the peptide on neurons and microglia. Increased expressing of RAGE in Alzheimer's disease brain indicates that it is relevant to the pathogenesis of neuronal dysfunction and death.
1,916 citations