Alzheimer Disease: Landreth G

Landreth G. · Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106, USA. · J Neuroimmune Pharmacol. · Pubmed #18040837 No free full text.

This publication has no abstract.

Landreth G, Jiang Q, Mandrekar S, Heneka M. · Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. · Neurotherapeutics. · Pubmed #18625459 links to  free full text

Abstract: Alzheimer's disease (AD) is characterized by the deposition of beta-amyloid within the brain parenchyma and is accompanied by the impairment of neuronal metabolism and function, leading to extensive neuronal loss. The disease involves the perturbation of synaptic function, energy, and lipid metabolism. The development of amyloid plaques results in the induction of a microglial-mediated inflammatory response. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor whose biological actions are to regulate glucose and lipid metabolism and suppress inflammatory gene expression. Thus, agonists of this receptor represent an attractive therapeutic target for AD. There is now an extensive body of evidence that has demonstrated the efficacy of PPARgamma agonists in ameliorating disease-related pathology and improved learning and memory in animal models of AD. Recent clinical trials of the PPARgamma agonist rosiglitazone have shown significant improvement in memory and cognition in AD patients. Thus, PPARgamma represents an important new therapeutic target in treating AD.

Landreth G. · Department of Neurosciences, Case Western Reserve University, School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106, USA. · Curr Alzheimer Res. · Pubmed #17430241 No free full text.

Abstract: Alzheimer's disease (AD) is a devastating neurodegenerative disease for which there are no highly effective therapies. A novel therapeutic approach to the treatment of AD is the use of agonists of the nuclear receptor, peroxisome proliferators-activated receptor gamma (PPARgamma). PPARgamma is a ligand activated transcription factor whose best described roles are to regulate lipid metabolism and inflammation. Agonists of PPARgamma have been shown to ameliorate AD-related pathology in animal models of AD and improve cognition. A number of potential mechanisms have been advanced to account for these effects. PPARgamma agonists act as insulin sensitizers, facilitating insulin action. In addition, PPARgamma agonists have been shown to inhibit inflammatory gene expression, alter Abeta homeostasis and exhibit neuroprotective effects. Importantly, recent clinical trials of FDA approved PPARgamma agonists have been shown to improve cognition and memory in AD patients. Thus, PPARgamma agonists represent a new and potentially efficacious treatment of AD.

Landreth G. · Department of Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA. · Exp Neurol. · Pubmed #16733054 No free full text.

This publication has no abstract.

Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T. · Sun Health Research Institute, 10515 West Santa Fe Drive, P.O. Box 1278, 85372, Sun City, AZ, USA. · Neurobiol Aging. · Pubmed #10858586 No free full text.

Abstract: Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.

Morgan D, Landreth G, Bickford P. · Department of Molecular Pharmacology and Physiology, School of Biomedical Sciences, College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, Tampa, FL 33612, USA. · J Neuroimmune Pharmacol. · Pubmed #18946741 No free full text.

Abstract: Alzheimer's disease (AD) is a critical health care problem that has considerable social and economic impact on society. Effective treatments have been elusive. One major causal factor for the disease is believed to be the deposition of amyloid fibrils in the brain, which ultimately leads to neurodegeneration and cognitive dysfunction. Based on the amyloid hypothesis of Alzheimer's disease, many therapies presently target the amyloid beta (Abeta) peptide, the monomeric protein fragment that assembles to form fibrils. This video article takes the form of a debate between Dr. Morgan and Dr. Landreth on the merits and drawbacks of an Alzheimer's disease vaccine. Click on Supplemental Material to watch the streaming video.

Ostrowski SM, Wilkinson BL, Golde TE, Landreth G. · Department of Neurosciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA. · J Biol Chem. · Pubmed #17646164 links to  free full text

Abstract: Epidemiological evidence suggests that long term treatment with hydroxymethylglutaryl-CoA reductase inhibitors, or statins, decreases the risk for developing Alzheimer disease (AD). However, statin-mediated AD protection cannot be fully explained by reduction of cholesterol levels. In addition to their cholesterol lowering effects, statins have pleiotropic actions and act to lower the concentrations of isoprenoid intermediates, such as geranylgeranyl pyrophosphate and farnesyl pyrophosphate. The Rho and Rab family small G-proteins require addition of these isoprenyl moieties at their C termini for normal GTPase function. In neuroblastoma cell lines, treatment with statins inhibits the membrane localization of Rho and Rab proteins at statin doses as low as 200 nm, without affecting cellular cholesterol levels. In addition, we show for the first time that at low, physiologically relevant, doses statins preferentially inhibit the isoprenylation of a subset of GTPases. The amyloid precursor protein (APP) is proteolytically cleaved to generate beta-amyloid (Abeta), which is the major component of senile plaques found in AD. We show that inhibition of protein isoprenylation by statins causes the accumulation of APP within the cell through inhibition of Rab family proteins involved in vesicular trafficking. Moreover, inhibition of Rho family protein function reduces levels of APP C-terminal fragments due to enhanced lysosomal dependent degradation. Statin inhibition of protein isoprenylation results in decreased Abeta secretion. In summary, we show that statins selectively inhibit GTPase isoprenylation at clinically relevant doses, leading to reduced Abeta production in an isoprenoid-dependent manner. These studies provide insight into the mechanisms by which statins may reduce AD pathogenesis.

Sastre M, Dewachter I, Rossner S, Bogdanovic N, Rosen E, Borghgraef P, Evert BO, Dumitrescu-Ozimek L, Thal DR, Landreth G, Walter J, Klockgether T, van Leuven F, Heneka MT. · Department of Neurology, University of Bonn, Sigmund Freud Strasse 25, 53127 Bonn, Germany. · Proc Natl Acad Sci U S A. · Pubmed #16407166 links to  free full text

Abstract: Epidemiological evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the risk for Alzheimer's disease (AD). Certain NSAIDs can activate the peroxisome proliferator-activated receptor-gamma (PPARgamma), which is a nuclear transcriptional regulator. Here we show that PPARgamma depletion potentiates beta-secretase [beta-site amyloid precursor protein cleaving enzyme (BACE1)] mRNA levels by increasing BACE1 gene promoter activity. Conversely, overexpression of PPARgamma, as well as NSAIDs and PPARgamma activators, reduced BACE1 gene promoter activity. These results suggested that PPARgamma could be a repressor of BACE1. We then identified a PPARgamma responsive element (PPRE) in the BACE1 gene promoter. Mutagenesis of the PPRE abolished the binding of PPARgamma to the PPRE and increased BACE1 gene promoter activity. Furthermore, proinflammatory cytokines decreased PPARgamma gene transcription, and this effect was supressed by NSAIDs. We also demonstrate that in vivo treatment with PPARgamma agonists increased PPARgamma and reduced BACE1 mRNA and intracellular beta-amyloid levels. Interestingly, brain extracts from AD patients showed decreased PPARgamma expression and binding to PPRE in the BACE1 gene promoter. Our data strongly support a major role of PPARgamma in the modulation of amyloid-beta generation by inflammation and suggest that the protective mechanism of NSAIDs in AD involves activation of PPARgamma and decreased BACE1 gene transcription.

Cordle A, Koenigsknecht-Talboo J, Wilkinson B, Limpert A, Landreth G. · Department of Neuroscience, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. · J Biol Chem. · Pubmed #16085653 links to  free full text

Abstract: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been reported to reduce the risk of Alzheimer disease. We have shown previously that statins inhibit a beta-amyloid (Abeta)-mediated inflammatory response through mechanisms independent of cholesterol reduction. Specifically, statins exert anti-inflammatory actions through their ability to prevent the isoprenylation of members of the Rho family of small G-proteins, resulting in the functional inactivation of these G-proteins. We report that statin treatment of microglia results in perturbation of the cytoskeleton and morphological changes due to alteration in Rho family function. Statins also block Abeta-stimulated phagocytosis through inhibition of Rac action. Paradoxically, the statin-mediated inactivation of G-protein function was associated with increased GTP loading of Rac and RhoA, and this effect was observed in myeloid lineage cells and other cell types. Statin treatment disrupted the interaction of Rac with its negative regulator the Rho guanine nucleotide dissociation inhibitor (RhoGDI), an interaction that is dependent on protein isoprenylation. We propose that lack of negative regulation accounts for the increased GTP loading. Isoprenylation of Rac is also required for efficient interaction with the plasma membrane, and we report that statin treatment dramatically reduces the capacity of Rac to interact with membranes. These results suggest a mechanism by which statins inhibit the actions of Rho GTPases and attenuate Abeta-stimulated inflammation.

Nekrasova T, Shive C, Gao Y, Kawamura K, Guardia R, Landreth G, Forsthuber TG. · Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106, USA. · J Immunol. · Pubmed #16081808 links to  free full text

Abstract: T cell activation engages multiple intracellular signaling cascades, including the ERK1/2 (p44/p42) pathway. It has been suggested that ERKs integrate TCR signal strength, and are important for thymocyte development and positive selection. However, the requirement of ERKs for the effector functions of peripheral mature T cells and, specifically, for T cell-mediated autoimmunity has not been established. Moreover, the specific requirements for ERK1 vs ERK2 in T cells have not been resolved. Therefore, we investigated the role of ERK1 in T cell immunity to foreign and self Ags and in the induction of experimental autoimmune encephalomyelitis. The results show that in ERK1-deficient (ERK1-/-) mice, the priming, proliferation, and cytokine secretion of T cells to the self Ag myelin oligodendrocyte glycoprotein peptide 35-55 and to the prototypic foreign Ag OVA are not impaired as compared with wild-type mice. Furthermore, ERK1-/- mice are highly susceptible to experimental autoimmune encephalomyelitis induced with myelin oligodendrocyte glycoprotein peptide 35-55. Finally, thymocyte development and mitogen-induced proliferation were not impaired in ERK1-/- mice on the inbred 129 Sv and C57BL/6 backgrounds. Collectively, the data show that ERK1 is not critical for the function of peripheral T cells in the response to self and foreign Ags and in T cell-mediated autoimmunity, and suggest that its loss can be compensated by ERK2.

Cordle A, Landreth G. · Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. · J Neurosci. · Pubmed #15647473 links to  free full text

Abstract: Alzheimer's disease (AD) is characterized by extracellular deposits of fibrillar beta-amyloid (Abeta) in the brain, a fulminant microglial-mediated inflammatory reaction, and neuronal death. The use of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) is associated with a reduced risk of AD, which has been attributed to the cholesterol-lowering actions of these drugs. Statins have been reported recently to have anti-inflammatory actions in addition to their classic lipid-lowering effects. We report that statins robustly inhibited the Abeta-stimulated expression of interleukin-1beta and inducible nitric oxide synthase and the production of nitric oxide by microglia and monocytes. Statin treatment also blocked the rac1-dependent activation of NADPH oxidase and superoxide production. The anti-inflammatory actions of the statins were attributable to their ability to reduce the levels of isoprenyl intermediates in the cholesterol biosynthetic pathway. The effect of statins could not be reversed by exogenous cholesterol supplementation, indicating that the anti-inflammatory actions are distinct from their cholesterol-lowering actions. The addition of the isoprenyl precursors, mevalonic acid, and geranylgeranyl pyrophosphate (GGpp) attenuated the statin-mediated downregulation of inflammatory markers. Prevention of protein isoprenylation by the GGpp transferase inhibitor (GGTI-286) or inhibition of Rho-family function with Clostridium difficile Toxin A blocked the inflammatory response similar to the effect of statin treatment. We argue that the statin-mediated decrease in AD risk arises from their pleiotropic actions, effecting a reduction in neuronal Abeta production and microglia-directed inflammation.

Koenigsknecht J, Landreth G. · Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. · J Neurosci. · Pubmed #15525768 links to  free full text

Abstract: Microglia are the principle immune effector and phagocytic cells in the CNS. These cells are associated with fibrillar beta-amyloid (fAbeta)-containing plaques found in the brains of Alzheimer's disease (AD) patients. The plaque-associated microglia undergo a phenotypic conversion into an activated phenotype and are responsible for the development of a focal inflammatory response that exacerbates and accelerates the disease process. Paradoxically, despite the presence of abundant activated microglia in the brain of AD patients, these cells fail to mount a phagocytic response to Abeta deposits but can efficiently phagocytose Abeta fibrils and plaques in vitro. We report that exposure of microglia to fAbeta in vitro induces phagocytosis through mechanisms distinct from those used by the classical phagocytic receptors, the Ig receptors (FcRgammaI and FcgammaRIII) or complement receptors. Microglia interact with fAbeta through a recently characterized Abeta cell surface receptor complex comprising the B-class scavenger receptor CD36, alpha6beta1 integrin, and CD47 (integrin-associated protein). Antagonists specific for each component of the receptor complex blocks fAbeta-stimulated phagocytosis. These data demonstrated that engagement of this ensemble of receptors is required for induction of phagocytosis. The phagocytic response stimulated by this receptor complex is driven principally by a beta(1) integrin-linked process that is morphologically and mechanistically distinct from the classical type I and type II phagocytic mechanisms. These data provide evidence for phagocytic uptake of fAbeta through a receptor-mediated, nonclassical phagocytic mechanism.

Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, Citron M, Landreth G. · Department of Neuroscience, Amgen Inc., Thousand Oaks, California 91320, USA. · J Neurosci. · Pubmed #12930788 links to  free full text

Abstract: Alzheimer's disease (AD) is characterized by a microglial-mediated inflammatory response elicited by extensive amyloid deposition in the brain. Nonsteroidal anti-inflammatory drug (NSAID) treatment reduces AD risk, slows disease progression, and reduces microglial activation; however, the basis of these effects is unknown. We report that treatment of 11-month-old Tg2576 mice overexpressing human amyloid precursor protein (APP) with the NSAID ibuprofen for 16 weeks resulted in the dramatic and selective reduction of SDS-soluble beta-amyloid (Abeta)42, whereas it had smaller effects on SDS-soluble Abeta40 levels. Ibuprofen treatment resulted in 60% reduction of amyloid plaque load in the cortex of these animals. In vitro studies using APP-expressing 293 cells showed that ibuprofen directly affected APP processing, specifically reducing the production of Abeta42. Ibuprofen treatment resulted in a significant reduction in microglial activation in the Tg2576 mice, as measured by CD45 and CD11b expression. NSAIDs activate the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma); however, a potent agonist of this receptor, pioglitazone, only modestly reduced SDS-soluble Abeta levels and did not affect amyloid plaque burden or microglia activation, indicating that PPARgamma activation is not involved in the Abeta lowering effect of NSAIDs. These data show that chronic NSAID treatment can reduce brain Abeta levels, amyloid plaque burden, and microglial activation in an animal model of Alzheimer's disease.