Current
Drug Targets-CNS & Neurological Disorders, Volume 4, No. 3, 2005
Contents
Amyloid-Associated
Disease Mechanisms in Alzheimer's Disease
Guest
Editor: Jeroen J.M. Hoozemans
Editorial
Pp.221-222
Jeroen
J.M. Hoozemans
The
Neuroinflammatory Response in Plaques and Amyloid Angiopathy in Alzheimer’s
Disease: Therapeutic Implications Pp.223-233
Amyloid
Associated Proteins in Alzheimer's and Prion Disease Pp.235-248
R.
Veerhuis, R.S. Boshuizen and A. Familian
Preventing
Activation of Receptor for Advanced Glycation Endproducts in Alzheimer’s
Disease Pp.249-266
L-F.
Lue, S.D. Yan, D.M. Stern and D.G. Walker
The
Nrf2-ARE Signalling Pathway: Promising Drug Target to Combat Oxidative Stress
in Neurodegenerative Disorders Pp.267-281
Freek
L. van Muiswinkel and H. Bea Kuiperij
Protein
Quality Control in Alzheimer’s Disease: A Fatal Saviour Pp.283-292
W.
Scheper and E.M. Hol
The
Expression of Cell Cycle Proteins in Neurons and its Relevance for Alzheimer´s
Disease Pp.293-306
Uwe
Ueberham and Thomas Arendt
The
Role of COX-1 and COX-2 in Alzheimer’s Disease Pathology and the Therapeutic
Potentials of Non-Steroidal Anti-Inflammatory Drugs Pp.307-315
Jeroen
J.M. Hoozemans and M. Kerry O’Banion
Abstracts
[Back to top] Editorial
Jeroen J.M. Hoozemans
Alzheimer’s disease (AD) is a progressive neurological and psychiatric disorder. Clinically, patients develop progressive failure of memory, loss of acquired skills leading to apraxia, agnosia and aphasia, and frequentl, disturbances in emotion. AD is the most common neurodegenerative disease and the most common cause of dementia. The pathological antecedents are believed to occur several decades before the clinical symptoms are observed. The neuropathological hallmarks are loss of neurons and synapses, and accumulation of abnormal fibrils in two fibrous lesions, the neurofibrillary tangle and the senile plaque.
In 1984, Glenner and Wong purified and characterized the amyloid b (Ab) peptide, the major component of the plaque-like deposits in AD brains [1]. Currently, the amyloid cascade hypothesis is the most favoured hypothesis within the field of Alzheimer’s disease research. The amyloid cascade hypothesis describes the concept that AD may be a primarily amyloiddriven process, with the neuritic tau-pathology (neurofibrillary tangles and neuropil threads) being an important secondary phenomenon that is closely correlated with the syndrome of dementia [2,3]. This view is strongly supported by the fact that all the three causal genes (APP, PS1, PS2) increase the propensity of Ab to aggregate and to form insoluble fibrils, thus accelerating the deposition of Ab. However, the presence of diffuse deposits of Ab in the cerebral cortex of nondemented elderly and in brain regions of AD patients not associated with clinical symptoms, such as the cerebellum, suggests that the deposition of Ab by itself is not sufficient to produce the AD clinical symptoms. Without being detrimental to the amyloid cascade hypothesis, the current hot topic issue addresses several disease mechanisms in AD that are (in)directly associated with the amyloid-driven pathological cascade.
This hot-topic issue will address following themes: neuroinflammation, oxidative stress, protein quality control and ectopic cell cycle protein expression in neurons. These disease mechanisms are considered to perpetuate the amyloid-driven pathological cascade (Fig. 1). It will become clear that they can 1) mediate amyloid precursor protein metabolism and Ab levels in AD brain, 2) influence the formation of fibrillar amyloid plaques, 3) mediate Ab associated neuroinflammation and 4) mediate Ab induced neurotoxicity. It will also become apparent that most of these processes are involved very early in disease pathogenesis.
The first reviews will discuss several disease mechanisms that occur in Alzheimer’s disease. Drs. Rozemuller, Van Gool and Eikelenboom will discuss the neuroinflammatory response associated with amyloid depositions. An interesting part of this review will be on the differences in neuroinflammatory reaction between Ab plaques in the neuropil and cerebral amyloid angiopathy, and the consequences of Ab vaccination as therapeutical strategy. Drs. Veerhuis, Familian and Boshuizen will discuss the role of amyloid associated proteins and their effect on amyloid plaque formation, microglial activation and neurotoxicity. Drs. Lue, Yan, Stern and Walker will review the role of the receptor for advanced glycation endproducts (RAGE) in AD, and discuss the potential for targeting RAGE to mediate microglia inflammatory responses, neuronal stress, and Ab transport at the blood brain barrier. Drs. Van Muiswinkel and Kuiperij will discuss how oxidative stress is involved in neurodegeneration and highlight the role of the Nrf2-ARE signalling pathway as an attractive therapeutic target for neurodegenerative diseases.
Most of the disease mechanisms discussed in this hot topic issue are next to AD also involved in other neurodegenerative diseases like Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Creutzfeld-Jakob disease (CJD). These diseases are commonly addressed as protein-misfolding-diseases. Drs. Scheper and Hol will discuss this theme and address the neurotoxicity of intracellular Ab oligomers and the role of protein quality control in AD pathogenesis. Ectopic cell cycle protein expression in neurons is one of the earliest features in AD pathogenesis. Drs. Ueberham and Arendt will discuss the potential role of these proteins beyond cell cycle regulation in AD. Finally, Drs. O’Banion and Hoozemans will review the role of cyclooxygenase in AD, and discuss the current perspective of the use of selective COX-2 inhibitors in the treatment of AD.
Although treated as separate issues, the disease mechanisms described show great overlap with each other. For drug development this consequently implicates that addressing a single target could have adverse effects in different disease mechanisms (as pointed out for Ab immunization and selective COX-2 inhibition). On the other hand, looking for a therapeutic strategy that targets several disease mechanisms (via combinations of therapeutics or non-selective therapeutics) would probably have the most effect on the clinical outcome and disease progression. Increased understanding of disease mechanisms involved in AD pathogenesis and neurodegeneration will eventually lead to the development of therapeutic strategies for the treatment of AD and other neurodegenerative diseases. Overall, we hope that this hot-topic issue gives an overview of the pathological processes in AD and the potential of different drug targets in AD pathology.
[Back to top] The
Neuroinflammatory Response in Plaques and Amyloid Angiopathy in Alzheimer’s
Disease: Therapeutic Implications
Annemieke J.M. Rozemuller, Willem A van Gool and Piet Eikelenboom
The amyloid plaques in Alzheimer’s disease (AD) brains are co-localised with a broad variety of inflammation-related proteins (complement proteins, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that the Ab depositions in the neuroparenchyma are closely associated with a locally-induced, non-immune-mediated chronic inflammatory response. Clinicopathological and neuroradiological data show that activation of microglia are a relatively early pathogenic event that precedes the process of severe neuropil destruction in patients. Recent gene findings (cDNA microarray) confirm the immunohistochemical findings of an early involvement of inflammatory and regenerative pathways in AD pathogenesis. Ab deposition, inflammation and regenerative mechanisms are also early pathogenic events in transgenic mice models harbouring the pathological AD mutations, while “later” neurodegenerative characteristics are not seen in these models.
Next to the plaques, Ab amyloid deposition is frequently found in the walls of cerebral vessels (cerebral amyloid angiopathy). Most common is the type of amyloid deposition in the walls of meningeal and mediumsized cortical arteries, and more rarely, microcapillary amyloid angiopathy (dyshoric angiopathy). Immunohistochemical studies show that in AD patients, the majority of the amyloid deposits in the walls of the larger vessels is not associated with a chronic inflammatory response in contrast to micro-capillary amyloid angiopathy. In this contribution, we will give an overview of the similarities and differences between the involvement of inflammatory mechanisms in vascular and plaque amyloid in AD and transgenic models. The implications of the reviewed studies for an inflammation-based therapeutical approach in AD will be discussed.
[Back to top] Amyloid
Associated Proteins in Alzheimer's and Prion Disease
R. Veerhuis, R.S. Boshuizen and A. Familian
Clustering of activated microglia in Ab 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 Ab and prion (PrP) peptides, including their potential to activate microglia, relate to Ab 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 Ab 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.
[Back to top] Preventing
Activation of Receptor for Advanced Glycation Endproducts in Alzheimer’s
Disease
L-F. Lue, S.D. Yan, D.M. Stern and D.G. Walker
Receptor for advanced glycation endproducts (RAGE), a member of the immunoglobulin superfamily, is a multi-ligand, cell surface receptor expressed by neurons, microglia, astrocytes, cerebral endothelial cells, pericytes, and smooth muscle cells. At least three major types of the RAGE isoforms (full length, C-truncated, and N-truncated) are present in human brains as a result of alternative splicing. Differential expression of each isoform may play a regulatory role in the physiological and pathophysiological functions of RAGE. Analysis of RAGE expression in non-demented and Alzheimer’s disease (AD) brains indicated that increases in RAGE protein and percentage of RAGE-expressing microglia paralleled the severity of disease. Ligands for RAGE in AD include amyloid b peptide (Ab), S100/calgranulins, advanced glycation endproductmodified proteins, and amphoterin.
Collective evidence from in vitro and in vivo studies supports that RAGE plays multiple roles in the pathogenesis of AD. The major features of RAGE activation in contributing to AD result from its interaction with Ab, from the positive feedback mechanisms driven by excess amounts of Ab, and combined with sustained elevated RAGE expression. The adverse consequences of RAGE interaction with Ab include perturbation of neuronal properties and functions, amplification of glial inflammatory responses, elevation of oxidative stress and amyloidosis, increased Ab influx at the blood brain barrier and vascular dysfunction, and induction of autoantibodies. In this article, we will review recent advances of RAGE and RAGE activation based on findings from cell cultures, animal models, and human brains. The potential for targeting RAGE mechanisms as therapeutic strategies for AD will be discussed.
[Back to top] The Nrf2-ARE
Signalling Pathway: Promising Drug Target to Combat Oxidative Stress in
Neurodegenerative Disorders
Freek
L. van Muiswinkel and H. Bea Kuiperij
A large body of evidence indicates that oxidative stress is a salient pathological feature in many neurodegenerative diseases, including Amyotrophic lateral sclerosis, Alzheimer’s disease, and Parkinson’s disease. In addition to signs of systemic oxidative stress, at the biochemical and neuropathological level, neuronal degeneration in these disorders has been shown to coincide with several markers of oxidative damage to lipids, nucleic acids, and proteins in affected brain regions. Neuroinflammatory processes, often associated with the induction of free radical generating enzymes and the accumulation of reactive astrocytes and microglial cells, are considered as a major source of oxidative stress. Given the pathogenic impact of oxidative stress and neuroinflammation, therapeutic strategies aimed to blunt these processes are considered an effective way to confer neuroprotection. Recently, the nuclear transcription factor Nrf2, that binds to the antioxidant response element (ARE) in gene promoters, has been reported to constitute a key regulatory factor in the coordinate induction of a battery of endogenous cytoprotective genes, including those encoding for both antioxidant- and anti-inflammatory proteins. In the present review, besides discussing recent evidence underscoring the thesis that the Nrf2-ARE signalling pathway is an attractive therapeutic target for neurodegenerative diseases, we advocate the view that chemopreventive agents might be suitable candidates to serve as lead compounds for the development of a new class of neuroprotective drugs.
[Back to top] Protein
Quality Control in Alzheimer’s Disease: A Fatal Saviour
W. Scheper and E.M. Hol
Aggregation of Ab plays a key role in the pathogenesis of Alzheimer’s disease. Although the highly structured Ab aggregates (fibrils) have long been thought to be the toxic form of Ab, recent evidence suggests that smaller, soluble intermediates in Ab aggregation are the real culprit. Because these oligomeric aggregates are already formed in the secretory pathway, this raises another issue: Is intra- or extracellular Ab involved in the pathogenic cascade?
Because aggregated proteins are very toxic, cells have developed quality control responses to deal with such proteins. A prime site for quality culum. Here, aberrant proteins are recognized and can be targeted for degradation to the cytosolic quality control system. In addition, there is accumulating evidence for quality control in other subcellular compartments in the cell. All quality control mechanisms are initially protective, but will become destructive after prolonged accumulation of aggregated proteins. This is enhanced by decreased efficiency of these systems during aging and therefore, these responses may play an important role in the pathogenesis of Alzheimer’s disease. In this review, we will discuss the role of protein quality control in the neurotoxicity of Ab.
[Back to top] The Expression
of Cell Cycle Proteins in Neurons and its Relevance for Alzheimer´s Disease
Uwe Ueberham and Thomas Arendt
Alzheimer´s disease is a chronic neurodegenerative disorder characterised by typical pathological hallmarks such as amyloid deposition, neurofibrillary tangles and disturbances in the expression of various cell cycle proteins. A current pathogenetic hypothesis suggests that neurons, forced by external and internal factors, leave the differentiated G0 phase and re-enter the cell cycle. This process results in neuronal dedifferentiation and apoptosis and might contribute to an increased phosphorylation of the tau protein. There are a number of reports, however, describing the expression of cell cycle proteins in rodent or human brain under normal non-disease conditions. This might indicate that cell cycle expression of proteins in neurons is of physiological rather than pathophysiological relevance. Therefore, it needs to be carefully analysed whether the expression of cell cycle regulators such as cyclin-dependent kinases, cyclins or cyclin-dependent kinase inhibitors in neurons is a pathological hallmark that allows to discriminate between normal and disease condition. Here we attempt to summarise recent evidence for a dysfunction of cell cycle regulators in Alzheimer´s disease, considering the potential functions of these molecules beyond cell cycle regulation.
[Back to top] The Role of
COX-1 and COX-2 in Alzheimer’s Disease Pathology and the Therapeutic Potentials
of Non-Steroidal Anti-Inflammatory Drugs
Jeroen J.M. Hoozemans and M. Kerry O’Banion
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 of the chronic inflammatory reaction in AD. The best-characterised action of NSAIDs is the inhibition of cyclooxygenase (COX). So far, clinical trials designed to inhibit inflammation or cyclooxygenase activity have failed in the treatment of AD patients. In this review we will focus on the role, expression and regulation of COX-1 and COX-2 in neurodegeneration and AD pathogenesis. Understanding the pathological, physiological and neuroprotective role of cyclooxygenase will contribute to the development of a therapy for the treatment or prevention of AD.