VU Research Portal Spot the difference Bossers, C.A.M. 2009 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Bossers, C. A. M. (2009). Spot the difference: microarray analysis of gene expression changes in Alzheimer's and Parkinson's Disease. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 11. Oct. 2021 Spot the difference: microarray analysis of gene expression changes in Alzheimer’s and Parkinson’s Disease The research described in this thesis was conducted at the Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sci- ences, Amsterdam, The Netherlands. The research was financially supported by a collaboration between the Netherlands Institute for Neuroscience and Solvay Phar- maceuticals. Leescommissie: dr. P. Broqua prof.dr. P. Heutink dr. P.A.C. ‘t Hoen prof.dr. H.P.H. Kremer prof.dr. A.B. Smit dr. G.C.M. Zondag Publication of this thesis was financially supported by: Solvay Pharmaceuticals Eurogentec Vrije Universiteit Nederlands Instituut voor Neurowetenschappen ISBN 978-94-90371-05-0 Book and cover design: Koen Bossers Print: Off Page, Amsterdam No part of this publication may be reproduced, stored of transmitted in any way with- out written permission from the author. VRIJE UNIVERSITEIT Spot the difference: microarray analysis of gene expression changes in Alzheimer’s and Parkinson’s Disease ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. L.M. Bouter, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de faculteit der Aard- en Levenswetenschappen op dinsdag 10 november 2009 om 10.45 uur in het auditorium van de universiteit, De Boelelaan 1105 door Conrad Antonius Martinus Bossers geboren te Nijmegen promotoren: prof.dr. J. Verhaagen prof.dr. D.F. Swaab prof.dr. C.G. Kruse Contents Chapter 1 General introduction 7 Bossers K, Verhaagen J, Swaab DF Chapter 2 Scope and outline 29 Chapter 3 Analysis of gene expression in Parkinson’s disease: possible 35 involvement of neurotrophic support and axon guidance in dopaminergic cell death Bossers K, Meerhoff G, Balesar R, van Dongen JW, Kruse CG, Swaab DF, Verhaagen J; (2009) Brain Pathol. 19, 91-107. Chapter 4 Intensity-based analysis of dual-color gene expression data 75 as an alternative to ratio-based analysis to enhance reproducibility Bossers K, Ylstra B, Brakenhoff RH, Smeets SJ, Verhaagen J, Van de Wiel MA; submitted Chapter 5 Gene expression changes in the human prefrontal cortex 99 during the progression of Alzheimer’s Disease Bossers K, Meerhoff G, Essing A, Van Dongen J, Houba P, Kruse CG, Verhaagen J, Swaab DF; submitted Chapter 6 A meta-analysis of microarray-based gene expression studies 135 in Alzheimer’s disease Bossers K, Heetveld S, Swaab DF, Verhaagen J; manuscript in preparation Chapter 7 Neurosteroid biosynthetic pathways changes in the 153 Alzheimer’s disease prefrontal cortex Luchetti S, Bossers K, Van de Bilt S, Agrapart V, Ramirez Morales R, Vanni Frajese G, Swaab DF; submitted Chapter 8 General discussion 175 Bossers K, Swaab DF, Verhaagen J List of references 207 Nederlandse samenvatting 229 Dankwoord 235 Curriculum vitae 237 chapter 1 General introduction Koen Bossers, Joost Verhaagen, Dick F. Swaab GeNerAl introduction 1. Introduction In a population that is growing older and older, it is difficult to underestimate the impact of age-related neurodegenerative disorders such as Parkinson’s Disease (PD) and Alzheimer’s Disease (AD). In particular, the absence of treatment options to effectively treat, or even slow down the progression of these disorders means that individuals diagnosed with AD or PD face a long and debilitating disease with an inevitably negative outcome. This introduction will first focus on the clinical and neuropathological characteristics of PD and AD. Subsequently, advances in the understanding of putative molecular mechanisms underlying neurodegenerative events, mostly based on studies of rare familial variants of PD and AD, will be dis- cussed. As mentioned, effective treatment regimes remain conspicuously absent, despite enormous research efforts during the last two decades. Therefore, the final part of this introduction will focus on new research strategies that might help to provide insight in the biological mechanisms that contribute to AD- or PD-associ- ated neurodegeneration. 2. Parkinson’s Disease Parkinson’s Disease (PD) is a severe movement disorder which is neuropathological- ly characterized by a dramatic and selective loss of dopaminergic (DAergic) neurons in the substantia nigra (SN). The clinical symptoms usually only arise when ~60% of the SN DAergic neurons is lost, and the levels of DA in the putamen are de- creased by as much as 80%. The disease course is progressive, and the incidence in- creases strongly with age: the overall incidence is 1:5000, which increases to ~1:800 at age 70 (reviewed in Dauer and Przedborski 2003). early in the disease course, PD motor symptoms can be effectively treated with DA replacement therapies. How- ever, this treatment is only symptomatic and does not halt disease progression. The molecular mechanisms underlying PD-associated neurodegeneration remain poorly understood. 2.1 Clinical features of PD Clinically, PD manifests itself as a movement disorder characterized by, amongst others, resting tremors, rigidity, difficulties with voluntary movement and postural instability. The quality of life of a PD patient is most severely affected by the distur- bances in voluntary movement. Patients often have problems initiating movements, and move more slowly (bradykinesia). Other notable movement disturbances in- clude a stooped posture, decreased volume of speaking (hypophonia) and reduced degree of facial expression (hypomimia). Not surprisingly, PD patients develop dif- ficulties in performing simple daily routines such as getting dressed and walking the dog. Furthermore, the combined effects of hypophonia, hypomimia and the fact that PD patients often take longer to reply to questions, can pose a serious hin- 9 chapter 1 drance to the patient’s social life. Also, depression and social withdrawal are often observed in PD patients (reijnders et al. 2008). Apart from motor symptoms, PD patients are at greater risk for developing cog- nitive defects and dementia. It has been reported that around one-third of newly- diagnosed PD patients without dementia are cognitively impaired in areas such as executive function and working memory (Foltynie et al. 2004). This impairment may result from disruption of striatofrontal connections such as the mesocortical DAergic system. Indeed, executive function performance depends on DA levels (lewis et al. 2005; Lange et al. 1995). Furthermore, ~30% of PD patients develop dementia (Aarsland et al. 2005). The strongest neuropathological correlate for this finding is a reduced cholinergic activity in the cortex, secondary to degeneration of the nucleus basalis of Meynert (Bosboom et al. 2004). The presence of lewy Body (lB, discussed below) pathology in limbic and frontal areas might also contribute to symptoms of dementia in PD. However, AD-associated neuropathological altera- tions are frequently co-existent with lB pathology (emre 2003). Thus, the exact neuropathological correlate with dementia in PD remains unclear. 2.2 Neuropathological features of PD The main neuropathological hallmark of PD is the selective loss of DAergic neurons in the SN. This is accompanied by two specific types of intraneuronal proteinacious inclusions: spindle- or threadlike lewy neurites (lN), and globular lewy bodies (lB) near the nucleus. However, the SN is not the only brain area affected in PD. In fact, PD-associated lesions appear in a precisely defined order in different brain areas, and the SN is only affected after the appearance of PD lesions in other brain areas. In 2003, Braak et al published a method for staging the progression of PD (Braak et al. 2003). The first two stages are characterized by lesions in the dorsal IX/X motor nucleus and/or the intermediate reticular zone (stage 1), followed by lesions in the raphe nuclei, gigantocellular reticular nucleus and the coereulus/sub- coereulus complex (stage 2). In stage 3, the SN, in particular the pars compacta, becomes affected. Cortical involvement only occurs in later stages: the first lesions appear in the mesocortex (stage 4), whereas pathology in the neocortex is only ob- served in stages 5 and 6. Although the SN is not the area where PD-associated lesions first appear, it is the most significantly affected area. The overall loss of neuromelanin-positive DAergic neurons in end-stage PD is ~80% (Damier et al. 1999), resulting in a dramatic re- duction of DA output via the nigrostriatal pathway to the target areas of the SN: the caudate nucleus and putamen. especially the DAergic innervation of the caudate nucleus is severely reduced. The motor disturbances observed in PD arise from the loss of DA input into the striatum. 10 GeNerAl introduction 2.3 Treatment strategies for PD As the main symptoms of PD arise from a reduced DA level in the striatum, it is not surprising that the main treatment strategy for PD is the replenishment of stri- atal DA levels (DA replacement therapy).