Cholesterol-independent neuroprotective and neurotoxic activities of statins: Perspectives for statin use in Alzheimer disease and other age-related neurodegenerative disorders

Butterfield, D. Allan; Barone, Eugenio; Mancuso, Cesare

doi:10.1016/j.phrs.2011.04.007

Cited by 68 publications

(51 citation statements)

References 95 publications

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“…Additionally, many studies have shown that Flu significantly reduces atherosclerotic area lesions [35], macrophage content [36,] TC plasma levels, and lipid accumulation in lesions in Rbs fed with high fat diet [37]. We chose to investigate this rather weak statin in view of the fact that it causes less glucose intolerance that “stronger” statins, in recent population studies [38,39].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Toll-Like Receptors 2, 3, 4, and 8 Is Correlated to the Vascular Atherosclerotic Process in the Hyperlipidemic Rabbit Model: The Effect of Statin Treatment

et al. 2017

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Background: Atherosclerosis is the major cause of cardiovascular disease; hypercholesterolemia is a major risk factor. We hypothesized that specific TLR members (TLR2, TLR3, TLR4, TLR8) may play a role in atherosclerosis progression and its accompanying inflammatory response. We determined the association of atherosclerotic lesions and TLR mRNA expression in different aortic sites. We also assessed the effects of fluvastatin (Flu) treatment on TLR expression and plaque characteristics. Methods: Male rabbits, fed with an atherogenic diet for a duration of 3 months, were screened for advanced atherosclerotic lesions in the aorta. Additional animals received normal diet or normal diet plus Flu for 1 additional month. TLR mRNA expression in various thoracic and abdominal aortic segments was assessed, together with atherosclerotic changes. Results: After high lipid diet, the atherosclerotic burden increased more in the abdominal than in the thoracic aorta; TLR2, 3, 4, and 8 also increased significantly. Flu decreased atherosclerotic plaque, calcium deposition, lipid cores, intraplaque hemorrhage, erythrocyte membranes, endothelial cells, and macrophage infiltration, while increasing smooth muscle cells in plaques of both aortic segments; it also lowered TLR2, 3, 4, and 8 expression in all aortic segments to a stronger degree than resumption of normal diet. There was a strong association between blood and tissue parameters during experimental period and finally a strong correlation found between these parameters with mRNA of TLR2, 3, 4, and 8 in various stages. Conclusion: For the first time TLR2, 3, 4, and 8 mRNA expression is prospectively explored after hypercholesterolemic diet in the rabbit model. TLR2, 3, 4, and 8 mRNA expression is strongly upregulated and correlates with the progression of atherosclerosis in the aorta. Flu significantly inhibited this progress and reduced inflammation via TLR downregulation which was strongly associated with regression of plaque morphology and atherosclerosis promoting factors.

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Section: Discussionmentioning

confidence: 99%

Overexpression of Toll-Like Receptors 2, 3, 4, and 8 Is Correlated to the Vascular Atherosclerotic Process in the Hyperlipidemic Rabbit Model: The Effect of Statin Treatment

et al. 2017

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“…42 Statins are known to have multiple physiologic effects in addition to their ability to reduce serum cholesterol levels including antioxidant, antinitrosative, and immunomodulatory properties. 43 It is possible that one or more of these pathways may be involved in its effect on dementia.…”

Section: Discussionmentioning

confidence: 99%

Statin Use, Incident Dementia and Alzheimer Disease in Elderly African Americans

et al. 2015

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Objective: To investigate the association between statin use, incident dementia, and Alzheimer disease (AD) in a prospective elderly African American cohort. Design:Two stage design with a screening interview followed by a comprehensive in-home assessment conducted over an eight-year period. Diagnoses of incident AD and dementia were made by consensus. Statin use was collected at each evaluation. Measurements of low-density lipoprotein cholesterol (LDL), C-reactive protein (CRP) and APOE genotype were obtained from baseline blood samples. Logistic regression models were used to test the association of statin use on incident dementia and AD and its possible association with lipid and CRP levels. Setting: Indianapolis, IndianaParticipants: From an original cohort of 2629 participants, a subsample of 974 African Americans aged >70 years with normal cognition, at least one follow up evaluation, complete statin information, and biomarker availability were included. Main Outcome Measures: Incident dementia and incident AD.Results: After controlling for age at diagnosis, sex, education level, presence of the APOE ε4 allele and history of stroke for the incident dementia model, baseline use of statins was associated with a significantly decreased risk of incident dementia (OR=.44, P=.029) and incident AD (OR=.40, P=.029). The significant effect of statin use on reduced AD risk and trend for dementia risk was found only for those participants who reported consistent use over the observational period (incident AD: P=.034; incident dementia: P=.061). Additional models found no significant interaction between baseline statin use, baseline LDL, or CRP level and incident dementia/AD.Conclusions: Consistent use of statin medications during eight years of followup resulted in significantly reduced risk for incident AD and a trend toward reduced risk for incident dementia. Ethn Dis.2015;25(3):345-354.

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“…The maximal statin concentration in blood plasma ranges between 10 and 448 ng/ml within 0.5-4 h after statin administration ( 28,29 ). We therefore analyzed induction of RAGE shedding via different statins at physiologically relevant concentrations.…”

Section: Treatment With Therapeutically Relevant Statin Concentrationsmentioning

confidence: 99%

Statins stimulate the production of a soluble form of the receptor for advanced glycation end products

Quade-Lyssy

Kanarek

Baiersdörfer

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org complications, atherosclerosis, and Alzheimer's disease (AD) ( 1 ). Proteins and peptides like advanced glycation end products (AGEs), amyloid-␤ peptides (A ␤ s), S100/ calgranulin family members, and HMGB1 (amphoterin) have been identifi ed as ligands for RAGE ( 2 ). Diabetes is characterized by a high blood glucose level. This enhanced concentration of glucose is responsible for the nonenzymatic generation of AGEs. AGEs represent a heterogeneous group of proteins, lipids, and nucleic acids resulting from chemical reactions between reducing sugars and amino groups. Studies with animal models have shown that RAGE is the best known target for AGEs in the vasculature and it is well established that the AGE/RAGE interaction contributes to the progression of atherosclerotic plaques ( 3-5 ). Ligand/RAGE interaction induces activation of various pro-infl ammatory and pro-atherogenic mediators, such as the nuclear factor-B (NF-B)-dependent mediators vascular cell adhesion molecule-1, tumor necrosis factor-␣ , interleukin-6, and RAGE ( 6 ). Because RAGE itself is regulated by NF-B, this further increases its expression and promotes cellular dysfunction ( 7 ).Blockade of RAGE by using the soluble form of the receptor ameliorates the vascular complications of diabetes in animal models ( 8-10 ) and suppresses the accumulation of A ␤ s in the brain of an AD mouse model ( 11 ). These benefi cial effects of soluble RAGE are thought to be mediated by trapping ligands, thus preventing ligand binding of membrane-bound RAGE. The circulating soluble form of RAGE containing only the extracellular part of fulllength RAGE, is either produced by alternative splicing The type I transmembrane protein receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, has been shown to play a crucial role in chronic infl ammatory diseases, late diabetic Press, August 21, 2013 DOI 10.1194 Statins stimulate the production of a soluble form of the receptor for advanced glycation end products Abbreviations: A ␤ , amyloid-␤ peptide; AD, Alzheimer's disease; AGE, advanced glycation end product; APP, amyloid precursor protein; esRAGE, endogenous secretory receptor for advanced glycation end products; FCS, fetal calf serum; LDS, lipid-defi cient serum; M ␤ CD, methyl-␤ -cyclodextrin; NF-B, nuclear factor-B; RAGE, receptor for advanced glycation end products; RNAi, RNA interference; siRNA, small interfering RNA; SQS, squalene synthase; sRAGE, shed receptor-the soluble form of the receptor for advanced glycation end products after proteolytic shedding of the full length receptor; ZA, zaragozic acid A . Published, JLR Papers in

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Cholesterol-independent neuroprotective and neurotoxic activities of statins: Perspectives for statin use in Alzheimer disease and other age-related neurodegenerative disorders

Cited by 68 publications

References 95 publications

Overexpression of Toll-Like Receptors 2, 3, 4, and 8 Is Correlated to the Vascular Atherosclerotic Process in the Hyperlipidemic Rabbit Model: The Effect of Statin Treatment

Overexpression of Toll-Like Receptors 2, 3, 4, and 8 Is Correlated to the Vascular Atherosclerotic Process in the Hyperlipidemic Rabbit Model: The Effect of Statin Treatment

Statin Use, Incident Dementia and Alzheimer Disease in Elderly African Americans

Statins stimulate the production of a soluble form of the receptor for advanced glycation end products

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