Alzheimer Disease: Veerhuis R

Hoozemans JJ, Rozemuller JM, van Haastert ES, Veerhuis R, Eikelenboom P. · Department of Pathology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. · Curr Pharm Des. · Pubmed #18537664 No free full text.

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of beta amyloid (Abeta) protein and the formation of neurofibrillary tangles. In addition, there is an increase of inflammatory proteins in the brains of AD patients. Epidemiological studies, indicating that non-steroidal anti-inflammatory drugs (NSAIDs) decrease the risk of developing AD, have encouraged the study on the role of inflammation in AD. The best-characterized action of most NSAIDs is the inhibition of cyclooxygenase (COX). The expression of the constitutively expressed COX-1 and the inflammatory induced COX-2 has been intensively investigated in AD brain and different disease models for AD. Despite these studies, clinical trials with NSAIDs or selective COX-2 inhibitors showed little or no effect on clinical progression of AD. The expression levels of COX-1 and COX-2 change in the different stages of AD pathology. In an early stage, when low-fibrillar Abeta deposits are present and only very few neurofibrillary tangles are observed in the cortical areas, COX-2 is increased in neurons. The increased neuronal COX-2 expression parallels and colocalizes with the expression of cell cycle proteins. COX-1 is primarily expressed in microglia, which are associated with fibrillar Abeta deposits. This suggests that in AD brain COX-1 and COX-2 are involved in inflammatory and regenerating pathways respectively. In this review we will discuss the role of COX-1 and COX-2 in the different stages of AD pathology. Understanding the physiological and pathological role of cyclooxygenase in AD pathology may facilitate the design of therapeutics for the treatment or prevention of AD.

Eikelenboom P, Veerhuis R, Scheper W, Rozemuller AJ, van Gool WA, Hoozemans JJ. · Department of Neurology, Academic Medical Center, University of Amsterdam, The Netherlands. · J Neural Transm. · Pubmed #17036175 No free full text.

Abstract: The interest of scientists in the involvement of inflammation-related mechanisms in the pathogenesis of Alzheimer's disease (AD) goes back to the work of one of the pioneers of the study of this disease. About hundred years ago Oskar Fischer stated that the crucial step in the plaque formation is the extracellular deposition of a foreign substance that provokes an inflammatory reaction followed by a regenerative response of the surrounding nerve fibers. Eighty years later immunohistochemical studies revealed that amyloid plaques are indeed co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. These findings have led to the view that the amyloid plaque is the nidus of a non-immune mediated chronic inflammatory response locally induced by fibrillar A beta deposits. Recent neuropathological studies show a close relationship between fibrillar A beta deposits, inflammation and neuroregeneration in relatively early stages of AD pathology preceding late AD stages characterized by extensive tau-related neurofibrillary changes. In the present work we will review the role of inflammation in the early stage of AD pathology and particularly the role of inflammation in A beta metabolism and deposition. We also discuss the possibilities of inflammation-based therapeutic strategies in AD.

Hoozemans JJ, Veerhuis R, Rozemuller JM, Eikelenboom P. · Department of Neuropathology, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 110DE Amsterdam, The Netherlands. · Int J Dev Neurosci. · Pubmed #16384684 No free full text.

Abstract: The initial stages of Alzheimer's disease pathology in the neocortex show upregulation of cell cycle proteins, adhesion and inflammation related factors, indicating the early involvement of inflammatory and regenerating pathways in Alzheimer's disease pathogenesis. These brain changes precede the neurofibrillary pathology and the extensive process of neurodestruction and (astro)gliosis. Amyloid beta deposition, inflammation and regenerative mechanisms are also early pathogenic events in transgenic mouse models harbouring the pathological Alzheimer's disease mutations, while neurodegenerative characteristics are not seen in these models. This review will discuss the relationship between neuroinflammation and neuroregeneration in the early stages of Alzheimer's disease pathogenesis.

Veerhuis R, Boshuizen RS, Familian A. · Institute for Clinical and Experimental Neurosciences-VU, Departments of Psychiatry Vrije Universiteit University Medical Center, 1007 MB Amsterdam, The Netherlands. · Curr Drug Targets CNS Neurol Disord. · Pubmed #15975027 No free full text.

Abstract: Clustering of activated microglia in Abeta deposits is related to accumulation of amyloid associated factors and precedes the neurodegenerative changes in AD. Microglia-derived pro-inflammatory cytokines are suggested to be the driving force in AD pathology. Inflammation-related proteins, including complement factors, acute-phase proteins, pro-inflammatory cytokines, that normally are locally produced at low levels, are increasingly synthesized in Alzheimer's disease (AD) brain. Similar to AD, in prion diseases (Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease and experimentally scrapie infected mouse brain) amyloid associated factors and activated glial cells accumulate in amyloid deposits of conformational changed prion protein (PrPres). Biological properties of Abeta and prion (PrP) peptides, including their potential to activate microglia, relate to Abeta and PrP peptide fibrillogenic abilities that are influenced by certain amyloid associated factors. However, since small oligomers of amyloid forming peptides are more toxic to neurons than large fibrils, certain amyloid associated factors that enhance fibril formation, may sequester the potentially harmful Abeta and PrP peptides from the neuronal microenvironment. In this review the positive and negative actions of amyloid associated factors on amyloid peptide fibril formation and on the fibrillation state related activation of microglia will be discussed. Insight in these mechanisms will enable the design of specific therapies to prevent neurodegenerative diseases in which amyloid accumulation and glial activation are prominent early features.

Blasko I, Stampfer-Kountchev M, Robatscher P, Veerhuis R, Eikelenboom P, Grubeck-Loebenstein B. · Department of Psychiatry, University Hospital of Innsbruck, Innsbruck, Austria. · Aging Cell. · Pubmed #15268750 No free full text.

Abstract: A huge amount of evidence has implicated amyloid beta (A beta) peptides and other derivatives of the amyloid precursor protein (beta APP) as central to the pathogenesis of Alzheimer's disease (AD). It is also widely recognized that age is the most important risk factor for AD and that the innate immune system plays a role in the development of neurodegeneration. Little is known, however, about the molecular mechanisms that underlie age-related changes of innate immunity and how they affect brain pathology. Aging is characteristically accompanied by a shift within innate immunity towards a pro-inflammatory status. Pro-inflammatory mediators such as tumour necrosis factor-alpha or interleukin-1 beta can then in combination with interferon-gamma be toxic on neurons and affect the metabolism of beta APP such that increased concentrations of amyloidogenic peptides are produced by neuronal cells as well as by astrocytes. A disturbed balance between the production and the degradation of A beta can trigger chronic inflammatory processes in microglial cells and astrocytes and thus initiate a vicious circle. This leads to a perpetuation of the disease.

Hoozemans JJ, Veerhuis R, Rozemuller AJ, Eikelenboom P. · Department of Pathology, Graduate School Neurosciences Amsterdam, Research Institute Neurosciences, VU university medical center, Amsterdam, The Netherlands. · Curr Drug Targets. · Pubmed #12866660 No free full text.

Abstract: Epidemiological studies indicate that anti-inflammatory drugs, especially the non-steroidal anti-inflammatory drugs (NSAIDs), decrease the risk of developing Alzheimer's disease (AD). Their beneficial effects may be due to interference in the chronic inflammatory reaction, that takes place in AD. The best-characterized action of NSAIDs is the inhibition of cyclooxygenase (COX). There is special interest for anti-inflammatory treatment of AD using selective COX-2 inhibitors. These inhibitors reduce the inflammatory reaction but lack the side effects observed with non-selective NSAIDs. So far, clinical trials designed to inhibit inflammation or COX-2 activity have failed in the treatment of AD patients. Several lines of evidence can explain the failures of the anti-inflammatory and anti-COX-2 trials on AD patients. In this review we will focus on the role, expression and regulation of COX-1 and COX-2 in AD brain. Understanding the role of COX in AD pathogenesis could contribute to the development of an anti-inflammatory therapy for the treatment or prevention of AD.

Hoozemans JJ, Veerhuis R, Rozemuller AJ, Eikelenboom P. · Department of Pathology, Graduate School of Neurosciences Amsterdam, Research Institute Neurosciences Vrije Universiteit, VU University Medical Center, The Netherlands. · Drugs Today (Barc). · Pubmed #12532179 No free full text.

Abstract: Alzheimer's disease is a chronic neurodegenerative disease causing progressive impairment of memory and other cognitive functions. A number of sequential events are suggested to be associated with different pathological aspects observed in Alzheimer's disease, the so-called amyloid cascade hypothesis. Mismetabolism of the beta-amyloid precursor protein, as a result of mutations in the amyloid precursor protein gene or as results of impaired cleavage, leads to the formation of nonfibrillar and fibrillar amyloid-beta deposits. Glial cells are attracted to and activated by these amyloid-beta deposits. After activation, these cells secrete inflammatory mediators and reactive oxygen species, which can aggravate the aggregation of amyloid-beta. Some of the products released by activated glial cells, as well as amyloid-beta itself, can induce or promote neurodegeneration. Several mechanisms, such as mitotic reentry, apoptosis and cytoskeletal changes are suggested to be involved in neuronal loss. This review will outline several pathological mechanisms in Alzheimer's disease as well as some means of therapeutic intervention following the amyloid cascade hypothesis.

Eikelenboom P, Bate C, Van Gool WA, Hoozemans JJ, Rozemuller JM, Veerhuis R, Williams A. · Department of Psychiatry, Graduate School of Neurosciences, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. · Glia. · Pubmed #12379910 No free full text.

Abstract: Alzheimer's disease (AD) and prion disease are characterized neuropathologically by extracellular deposits of Abeta and PrP amyloid fibrils, respectively. In both disorders, these cerebral amyloid deposits are co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase protein, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that the cerebral Abeta and PrP deposits are closely associated with a locally induced, non-immune-mediated chronic inflammatory response. Epidemiological studies indicate that polymorphisms of certain cytokines and acute-phase proteins, which are associated with Abeta plaques, are genetic risk factors for AD. Transgenic mice studies have established the role of amyloid associated acute-phase proteins in Alzheimer amyloid formation. In contrast to AD, there is a lack of evidence that cytokines and acute-phase proteins can influence disease progression in prion disease. Clinicopathological and neuroradiological studies have shown that activation of microglia is a relatively early pathogenetic event that precedes the process of neuropil destruction in AD patients. It has also been found that the onset of microglial activation coincided in mouse models of prion disease with the earliest changes in neuronal morphology, many weeks before neuronal loss and subsequent clinical signs of disease. In the present work, we review the similarities and differences between the involvement of inflammatory mechanisms in AD and prion disease. We also discuss the concept that the demonstration of a chronic inflammatory-like process relatively early in the pathological cascade of both diseases suggests potential therapeutic strategies to prevent or to retard these chronic neurodegenerative disorders.

Hoozemans JJ, Rozemuller AJ, Veerhuis R, Eikelenboom P. · Department of Psychiatry, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. · BioDrugs. · Pubmed #11437695 No free full text.

Abstract: Alzheimer's disease (AD) is a chronic neurodegenerative disease causing progressive impairment of memory and cognitive function. The amyloid cascade hypothesis suggests that mismetabolism of the beta-amyloid (A beta) precursor protein (APP) followed by subsequent formation of non-fibrillar and fibrillar A beta deposits leads to glial activation and eventually to neurotoxicity, causing cognitive impairment. Several lines of evidence indicate that an inflammatory process contributes to the pathology of AD. First, inflammatory proteins have been identified as being associated with neuritic plaques and in glial cells surrounding these plaques. Second, certain polymorphisms of acute-phase proteins and cytokines associated with AD plaques increase the risk or predispose for earlier onset of developing AD. Third, epidemiological studies indicate that anti-inflammatory drugs can retard the development of AD. Several steps in the pathological cascade of AD have been identified as possible targets for actions of nonsteroidal anti-inflammatory drugs. For instance, microglia are considered a target because this cell type is closely involved in AD pathology through secretion of neurotoxic substances and by modulating a positive feedback loop of the inflammatory mechanism that may be involved in the pathological cascade in AD. On the basis of studies in APP transgenic mice, immunisation with A beta was recently suggested as a novel immunological approach for the treatment of AD. Immunisation elicits A beta-specific antibodies that could affect several early steps of the amyloid-driven cascade. Antibodies could prevent A beta from aggregating into fibrils and accelerate clearance of A beta by stimulating its removal by microglial cells. This review outlines the pathological and genetic evidence that an inflammatory mechanism is involved in AD and the therapeutic approaches based on inhibition or mediation of inflammation.

Blasko I, Ransmayr G, Veerhuis R, Eikelenboom P, Grubeck-Loebenstein B. · Department of Neurology, University Hospital of Innsbruck, Innsbruck, Austria. · J Neuroimmunol. · Pubmed #11311323 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.

Eikelenboom P, Rozemuller AJ, Hoozemans JJ, Veerhuis R, van Gool WA. · Research Institute Neurosciences Vrije Universiteit, Department of Psychiatry, Valeriuskliniek, Amsterdam, The Netherlands. · Alzheimer Dis Assoc Disord. · Pubmed #10850731 No free full text.

Abstract: In Alzheimer disease brains, the amyloid plaques are closely associated with a locally induced, nonimmune-mediated, chronic inflammatory response without any apparent influx of leukocytes from the blood. The present findings indicate that in cerebral A beta diseases (Alzheimer disease, Down syndrome, hereditary cerebral hemorrhage with amyloidosis-Dutch type), the clinical symptoms are determined to a great extent by the site of inflammatory response. It was found that the formation of the amyloid-microglia complex seems to be a relatively early pathogenic event that precedes the process of severe destruction of the neuropil. The idea that inflammation is implicated in Alzheimer pathology has received support from the epidemiologic studies indicating that the use of anti-inflammatory drugs can prevent or retard the Alzheimer disease process. In this contribution, we review the relationship between inflammation and clinical manifestation and the opportunities for anti-inflammatory treatments in Alzheimer disease.

Eikelenboom P, Veerhuis R. · Graduate School of Neurosciences Amsterdam, Research Institute Neurosciences Vrije Universiteit, Department of Psychiatry, Valeriuskliniek, The Netherlands. · Exp Gerontol. · Pubmed #10433400 No free full text.

Abstract: A variety of inflammatory proteins has been identified in brains of patients with Alzheimer's disease. The current data suggest that the inflammatory processes are intimately involved in several crucial events in the pathological cascade. Immunohistochemical studies reveal that those parts of the brain wherein the amyloid-beta deposits are closely associated with a chronic inflammatory response are strongly related to the characteristic symptoms. An inflammation-based approach could also provide a valuable theoretical framework to study the influence of extracerebral factors (such as acute phase reactants) on the clinical course of Alzheimer's disease.

Nielsen HM, Veerhuis R, Holmqvist B, Janciauskiene S. · Department of Clinical Chemistry, Pathology, The Alzheimer Centre, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. · Glia. · Pubmed #19062178 No free full text.

Abstract: Clearance of the amyloid-beta peptide (A beta) as a remedy for Alzheimer's disease (AD) is a major target in on-going clinical trials. In vitro studies confirmed that A beta is taken up by rodent astrocytes, but knowledge on human astrocyte-mediated A beta clearance is sparse. Therefore, by means of flow cytometry and confocal laser scanning microscopy (CLSM), we evaluated the binding and internalization of A beta1-42 by primary human fetal astrocytes and adult astrocytes, isolated from nondemented subjects (n = 8) and AD subjects (n = 6). Furthermore, we analyzed whether alpha1-antichymotrypsin (ACT), which is found in amyloid plaques and can influence A beta fibrillogenesis, affects the A beta uptake by human astrocytes. Upon over night exposure of astrocytes to FAM-labeled A beta1-42 (10 microM) preparations, (80.7 +/- 17.7)% fetal and (52.9 +/- 20.9)% adult A beta-positive astrocytes (P = 0.018) were observed. No significant difference was found in A beta1-42 uptake between AD and non-AD astrocytes, and no influence of ApoE genotype on A beta1-42 uptake was observed in any group. There was no difference in the percentage of A beta-positive cells upon exposure to A beta1-42 (10 microM) combined with ACT (1,000:1, 100:1, and 10:1 molar ratio), versus A beta1-42 alone. CLSM revealed binding of A beta1-42 to the cellular surfaces and cellular internalization of smaller A beta1-42 fragments. Under these conditions, there was no increase in cellular release of the proinflammatory chemokine monocyte-chemoattractant protein 1, as compared with nontreated control astrocytes. Thus, primary human astrocytes derived from different sources can bind and internalize A beta1-42, and fetal astrocytes were more efficient in A beta1-42 uptake than adult astrocytes.

Verwey NA, Schuitemaker A, van der Flier WM, Mulder SD, Mulder C, Hack CE, Scheltens P, Blankenstein MA, Veerhuis R. · Department of Neurology, Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands. · Dement Geriatr Cogn Disord. · Pubmed #19052452 No free full text.

Abstract: BACKGROUND: Serum amyloid P component (SAP), present in amyloid-beta (Abeta) plaques in Alzheimer's disease (AD), may protect Abeta deposits against proteolysis, thereby promoting plaque formation. The aim was to investigate if SAP levels in cerebrospinal fluid (CSF) and serum can be used to discriminate controls, AD and mild cognitive impairment (MCI) patients, and to identify incipient AD among MCI patients. METHODS: SAP levels in CSF and serum were determined in 30 controls, 67 MCI and 144 AD patients. At follow-up, 39 MCI patients had progressed to dementia, while 25 had remained stable (mean follow-up time: 2.6 +/- 1.0 and 2.1 +/- 0.8 years). RESULTS: Cross-sectionally no differences were found in SAP levels in CSF and serum between the groups. MCI patients that had progressed to dementia at follow-up had lower CSF SAP levels (13 mg/l, range 3.3-199.3 mg/l) than MCI nonprogressors (20.2 mg/l, range 7.0-127.7 mg/l; p < 0.05). A low CSF SAP level was associated with a 2-fold increased risk of progression to AD (hazard ratio = 2.2; 95% confidence interval = 0.9-5.4). CONCLUSION: Our data suggest that measurement of CSF SAP levels can aid in the identification of incipient AD among MCI patients.

Chafekar SM, Zwart R, Veerhuis R, Vanderstichele H, Baas F, Scheper W. · Neurogenetics Laboratory, VU university medical center, 1081 HV Amsterdam, The Netherlands. · Curr Alzheimer Res. · Pubmed #18855588 No free full text.

Abstract: Alzheimer's disease (AD) is characterized by the aggregation and subsequent deposition of misfolded beta-amyloid (Abeta) peptide. The unfolded protein response (UPR) is activated by misfolded protein stress in the endoplasmic reticulum (ER). In previous studies we demonstrated mild activation of the UPR by extracellularly applied oligomeric but not fibrillar Abeta1-42. In addition, we showed that oligomeric Abeta1-42 is internalized by cells, whereas fibrillar Abeta1-42 remains on the outside of the cell. Inhibition of Abeta uptake specifically inhibits toxicity of Abeta1-42 oligomers, underscoring the toxic potential of intracellular Abeta. Therefore, in the present study, we investigated the connection between intracellularly produced Abeta and the ER stress response, using human neuroblastoma cells overexpressing either wild type APP695 (APPwt) or APP695V717F (APPmut). Both cell lines secrete higher levels of Abeta1-40 and Abeta1-42 compared to the parental line. In addition, APPmut produces more Abeta1-42 than APPwt. Whereas the basal levels of UPR markers are not different, we find augmented UPR induction in response to ER stress in both APP overproducing cell lines compared to the parental cell line, with the strongest UPR activation in APPmut cells. In addition, ER stress toxicity was highest in APPmut cells, strongly suggesting a connection with the production of Abeta1-42. The difference in ER stress mediated toxicity between the APPwt and APPmut cell lines is alleviated by pretreatment with gamma-secretase inhibitor, indicating that it is dependent on Abeta production and in particular on Abeta1-42. Our data indicate that increased Abeta1-42 production sensitizes neuroblastoma cells for ER stress toxicity.

Trouw LA, Nielsen HM, Minthon L, Londos E, Landberg G, Veerhuis R, Janciauskiene S, Blom AM. · Department of Laboratory Medicine, Lund University, Malmö, Sweden. · Mol Immunol. · Pubmed #18556068 No free full text.

Abstract: In the Alzheimer's disease (AD) brain, binding of Clq within the Cl complex, the initiating molecule of the classical complement pathway, to apoptotic cells, DNA and amyloid-beta (Abeta), the major constituent of senile plaques, can initiate complement activation. However, the extent of activation is determined by the balance between activation and inhibition. Fluid-phase complement inhibitor C4b-binding protein (C4BP) was immunohistochemically detected in Abeta plaques and on apoptotic cells in AD brain. In vitro, C4BP bound apoptotic and necrotic but not viable brain cells (astrocytes, neurons and oligodendrocytes) and limited complement activation on dead brain cells. C4BP also bound Abeta1-42 peptide directly, via the C4BP alpha-chain, and limited the extent of complement activation by Abeta. C4BP levels in cerebrospinal fluid (CSF) of dementia patients and controls were low compared to levels in plasma and correlated with CSF levels of other inflammation-related factors. In conclusion, C4BP binds to dead brain cells and Abeta peptide in vitro, is present in CSF and possibly protects against excessive complement activation in AD brains.

Wilhelmus MM, Otte-Höller I, van Triel JJ, Veerhuis R, Maat-Schieman ML, Bu G, de Waal RM, Verbeek MM. · Department of Neurology and Alzheimer Center, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. · Am J Pathol. · Pubmed #18055545 links to  free full text

Abstract: Inefficient clearance of A beta, caused by impaired blood-brain barrier crossing into the circulation, seems to be a major cause of A beta accumulation in the brain of late-onset Alzheimer's disease patients and hereditary cerebral hemorrhage with amyloidosis Dutch type. We observed association of receptor for advanced glycation end products, CD36, and low-density lipoprotein receptor (LDLR) with cerebral amyloid angiopathy in both Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis Dutch type brains and increased low-density lipoprotein receptor-related protein-1 (LRP-1) expression by perivascular cells in cerebral amyloid angiopathy. We investigated if these A beta receptors are involved in A beta internalization and in A beta-mediated cell death of human cerebrovascular cells and astrocytes. Expression of both the LRP-1 and LDLR by human brain pericytes and leptomeningeal smooth muscle cells, but not by astrocytes, increased on incubation with A beta. Receptor-associated protein specifically inhibited A beta-mediated up-regulation of LRP-1, but not of LDLR, and receptor-associated protein also decreased A beta internalization and A beta-mediated cell death. We conclude that especially LRP-1 and, to a minor extent, LDLR are involved in A beta internalization by and A beta-mediated cell death of cerebral perivascular cells. Although perivascular cells may adapt their A beta internalization capacity to the levels of A beta present, saturated LRP-1/LDLR-mediated uptake of A beta results in degeneration of perivascular cells.

Wilhelmus MM, Boelens WC, Kox M, Maat-Schieman ML, Veerhuis R, de Waal RM, Verbeek MM. · Department of Neurology and Alzheimer Centre, Radboud University Nijmegen Medical Centre, The Netherlands. · Neurobiol Aging. · Pubmed #17629591 No free full text.

Abstract: In hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), severe cerebral amyloid angiopathy (CAA) is associated with an inflammatory reaction. Small heat shock proteins (sHsps) are molecular chaperones and association of HspB8 with CAA in HCHWA-D has been observed. The aims of this study were to investigate (1) if other sHsps are associated with the pathological lesions in HCHWA-D brains, (2) if the amyloid-beta protein (A beta) increases production of sHsps in cultured cerebral cells and (3) if sHsps are involved in the cerebral inflammatory processes in both Alzheimer's disease (AD) and HCHWA-D. We conclude that Hsp20, HspB8 and HspB2 are present in CAA in HCHWA-D, and that A beta did not affect cellular sHsps expression in cultured human brain pericytes and astrocytes. In addition, we demonstrated that Hsp20, HspB2 and HspB8 induced interleukin-6 production in cultured pericytes and astrocytes, which could be antagonized by dexamethasone, whereas other sHsps and A beta were inactive, suggesting that sHsps may be among the key mediators of the local inflammatory response associated with HCHWA-D and AD lesions.

Pijnenburg YA, Schoonenboom SN, Mehta PD, Mehta SP, Mulder C, Veerhuis R, Blankenstein MA, Scheltens P. · Alzheimer Centre and Department of Neurology, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · J Neurol Neurosurg Psychiatry. · Pubmed #17371907 No free full text.

Abstract: The role of amyloid metabolism in the pathophysiology of frontotemporal lobar degeneration (FTLD) has yet to be elucidated. We compared CSF levels of amyloid beta 1-40 (Abeta40) and amyloid beta 1-42 (Abeta42) in patients with FTLD (n = 21) versus patients with Alzheimer's disease (AD, n = 39) and in control subjects (n = 30). While in AD cases Abeta42 levels were lower and CSF Abeta40 levels equal to those in controls, a significant decrease in Abeta40 and increase in the CSF Abeta42/Abeta40 ratio was observed in FTLD compared with AD and control subjects. These findings favour a differential involvement of amyloid beta peptides in FTLD compared with AD.

Copani A, Hoozemans JJ, Caraci F, Calafiore M, Van Haastert ES, Veerhuis R, Rozemuller AJ, Aronica E, Sortino MA, Nicoletti F. · Department of Pharmaceutical Sciences, University of Catania, 95125 Catania, Italy. · J Neurosci. · Pubmed #17065437 links to  free full text

Abstract: Cultured neurons exposed to synthetic beta-amyloid (Abeta) fragments reenter the cell cycle and initiate a pathway of DNA replication that involves the repair enzyme DNA polymerase-beta (DNA pol-beta) before undergoing apoptotic death. In this study, by performing coimmunoprecipitation experiments on cross-linked nucleoprotein fragments from Abeta-treated neurons, we demonstrate that DNA pol-beta coimmunoprecipitates with cell division cycle 45 (Cdc45) and with DNA primase in short nucleoprotein fragments. This indicates that DNA pol-beta is loaded into neuronal DNA replication forks after Abeta treatment. In response to Abeta the canonical DNA-synthesizing enzyme DNA pol-delta also was loaded into neuronal replication forks, but at later times than DNA pol-beta. Methoxyamine, an inhibitor of the apurinic/apyrimidinic endonuclease that allows for the recruitment of DNA pol-beta during the process of base excision repair (BER), failed to affect coimmunoprecipitation between DNA pol-beta and Cdc45, indicating that DNA pol-beta loading to the replication forks is independent of DNA breaks. However, methoxyamine reduced DNA replication and ensuing apoptosis in neurons exposed to Abeta, suggesting that an efficient BER process allows DNA replication to proceed up to the threshold for death. These data demonstrate that DNA pol-beta is an essential component of the DNA replication machinery in Abeta-treated neurons and additionally support the hypothesis of a close association of cell cycle events with neuronal death in Alzheimer's disease (AD). Accordingly, by investigating the neuronal expression of DNA pol-beta, along with phosphorylated retinoblastoma protein and neurofibrillary changes in AD brain, we show an early involvement of DNA pol-beta in the pathogenesis of AD.

Hoozemans JJ, Stieler J, van Haastert ES, Veerhuis R, Rozemuller AJ, Baas F, Eikelenboom P, Arendt T, Scheper W. · Department of Neuropathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · Exp Gerontol. · Pubmed #16564150 No free full text.

Abstract: Alzheimer's disease (AD) is characterized by the accumulation and aggregation of misfolded proteins. The presence of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the unfolded protein response (UPR). Previously, we have shown that the UPR is activated in AD neurons. In actively dividing cells, activation of the UPR is accompanied by decreased cell cycle protein expression and an arrest in the G1 phase of the cell cycle. Aberrant expression of cell cycle proteins has been observed in post mitotic neurons in AD and is suggested to be involved in neurodegeneration. In this study we show that the protein levels of BiP/GRP78, an ER-stress marker, is increased in Braak stages B and C for amyloid deposits. This is in contrast to the levels of cell cycle markers cyclin D1, cyclin E and phosphorylated retinoblastoma protein (ppRb) which are decreased in Braak stage C compared to Braak stage A for amyloid deposits. In addition, we report a negative correlation between neuronal expression of ppRb and expression levels of BiP/GRP78 in control and AD cases. Activation of the UPR in neuronal cells induces changes in cell cycle protein expression similar to these observed in AD brain. ER stress inducers tunicamycin and thapsigargin down-regulate cell cycle proteins ppRb and cyclin D1 in differentiated neuroblastoma cells. In contrast, protein levels of p27, a cyclin dependent kinase inhibitor, are increased after induction of ER-stress using tunicamycin. These data suggest that activation of the UPR affects cell cycle protein expression in neurons during neurodegeneration in AD.

Hüll M, Müksch B, Akundi RS, Waschbisch A, Hoozemans JJ, Veerhuis R, Fiebich BL. · Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Hauptstrasse 5, D-79104 Freiburg, Germany. · Neurochem Int. · Pubmed #16546299 No free full text.

Abstract: Prostaglandins (PGs) are generated by the enzymatic activity of cyclooxygenase-1 and -2 (COX-1/2) and modulate several functions in the CNS such as the generation of fever, the sleep/wake cycle, and the perception of pain. Moreover, the induction of COX-2 and the generation of PGs has been linked to neuroinflammatory aspects of Alzheimer's disease (AD). Non-steroidal anti-inflammatory drugs (NSAIDs) that block COX enzymatic activity have been shown to reduce the incidence of AD in various epidemiological studies. While several reports investigated the expression of COX-2 in neurons and microglia, expression of COX-2 in astroglial cells has not been investigated in detail. Here we show that amyloid beta peptide 25-35 (Abeta(25-35)) induces COX-2 mRNA and protein synthesis and a subsequent release of prostaglandin E(2) (PGE(2)) in primary midbrain astrocytes. We further demonstrate that protein kinase C (PKC) is involved in Abeta(25-35)-induced COX-2/PGE(2) synthesis. PKC-inhibitors prevent Abeta(25-35)-induced COX-2 and PGE(2) synthesis. Furthermore Abeta(25-35) rapidly induces the phosphorylation and enzymatic activation of PKC in primary rat midbrain glial cells and in primary human astrocytes from post mortem tissue. Our data suggest that the PKC isoforms alpha and/or beta are most probably involved in Abeta(25-35)-induced expression of COX-2 in midbrain astrocytes. The potential role of astroglial cells in the phagocytosis of amyloid and the involvement of PGs in this process suggests that a modulation of PGs synthesis may be a putative target in the prevention of amyloid deposition.

Hoozemans JJ, Veerhuis R, Van Haastert ES, Rozemuller JM, Baas F, Eikelenboom P, Scheper W. · Neurogenetics Laboratory, Academic Medical Center, University of Amsterdam, P.O. Box 22660, 1100 DD, Amsterdam, The Netherlands. · Acta Neuropathol. · Pubmed #15973543 No free full text.

Abstract: Alzheimer's disease (AD) is, at the neuropathological level, characterized by the accumulation and aggregation of misfolded proteins. The presence of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the unfolded protein response (UPR) that may protect the cell against the toxic buildup of misfolded proteins. In this study we investigated the activation of the UPR in AD. Protein levels of BiP/GRP78, a molecular chaperone which is up-regulated during the UPR, was found to be increased in AD temporal cortex and hippocampus as determined by Western blot analysis. At the immunohistochemical level intensified staining of BiP/GRP78 was observed in AD, which did not co-localize with AT8-positive neurofibrillary tangles. In addition, we performed immunohistochemistry for phosphorylated (activated) pancreatic ER kinase (p-PERK), an ER kinase which is activated during the UPR. p-PERK was observed in neurons in AD patients, but not in non-demented control cases and did not co-localize with AT8-positive tangles. Overall, these data show that the UPR is activated in AD, and the increased occurrence of BiP/GRP78 and p-PERK in cytologically normal-appearing neurons suggest a role for the UPR early in AD neurodegeneration. Although the initial participation of the UPR in AD pathogenesis might be neuroprotective, sustained activation of the UPR in AD might initiate or mediate neurodegeneration.

Hoozemans JJ, Veerhuis R, Rozemuller AJ, Arendt T, Eikelenboom P. · Department of Psychiatry, Graduate School Neurosciences Amsterdam, Research Institute Neurosciences, VU University Medical Center, Amsterdam, The Netherlands. · Neurobiol Dis. · Pubmed #15056456 No free full text.

Abstract: In Alzheimer's disease (AD) brain, increased levels of cyclooxygenase-2 (COX-2), cell cycle markers, and p38 MAP kinase (MAPK) can be detected in neuronal cells. Besides mediating COX-2 expression, p38 MAPK is suggested to mediate cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). In this study, we show that neuronal immunoreactivity for phosphorylated p38 MAPK does not correlate with COX-2 or phosphorylated pRb (ppRb) in control and AD temporal cortex. Immunoreactivity for activated p38 MAPK co-localizes with AT8 immunoreactivity and increases with the occurrence of neurofibrillary tangles and plaques. On the other hand, COX-2 immunoreactivity co-localizes and correlates with ppRb immunoreactivity in pyramidal neurons. COX-2 and ppRb do not co-localize with AT8 and decrease with increasing pathology. These results suggest that p38 MAPK does not mediate COX-2 expression and pRb inactivation, which are involved in cellular changes in pyramidal neurons early in AD pathogenesis.