Title Promoter Affiliations Abstract "Stichting Alzheimer SAO-FRA: ""Herpesvirus-induced neuroinflammation in the peripheral nervous system (PNS) as a 'distant' trigger of Alzheimer's disease""" "Kathlyn Laval" "Department of Translational Physiology, Infectiology and Public Health" "Alzheimer’s disease (AD) is a neurodegenerative disorder affecting 26 million people worldwide. To date, there is no cure and current therapies are not effective in delaying progression. Thus, there is an urgent need to change the way of looking at the disease and to rethink possible therapies. Herpes simplex virus type 1 (HSV1) has recently received growing attention for its role in AD. HSV1 infects the mouth and invades peripheral sensory nerves. The virus remains inactive in sensory neurons but when a person is stressed, it can reactivate and return to the mouth, resulting in cold sores. Occasionally, the virus spreads from peripheral neurons to the brain after reactivation. The objective of HERPINAD is to provide a clear understanding of how common HSV1 infection plays a role in the initiation of AD. The hypothesis is that HSV1 infection of peripheral neurons causes inflammation which is relayed to neurons in the brain, resulting in long-term inflammation and neurodegeneration. This neuroinflammation represents the driving force of AD pathology, starting very early in the course of the disease. The paradigm shift will focus on the peripheral nervous system and will be away from the current thinking that the brain is directly infected by HSV1. This work will be performed using our new mouse model to study herpesvirusinduced neuroinflammation. Our findings will be of key importance for the design of new therapies that may prevent AD to the current and future generations." "Role y-secretase heterogeneity in intracellular AB production, lysosomal toxicity, and pathogenesis: contribution of familial Alzheimer’s disease mutations in presenilins and late onset Alzheimer’s disease risk factors" "Wim Annaert" "Laboratory of Membrane Trafficking (VIB-KU Leuven)" "Alzheimer’s disease (AD) is characterized by amyloid β (Aβ) plaques and tangles. These hallmarks appear relatively late in disease stirring the debate whether they are a consequence of earlier pathogenic processes. Herein intracellular Aβ accumulation precede their formation, and correlates better with synaptic dysfunction and cognitive decline. Our recent data suggest that the composition of Aβ yielding γ-secretase complexes plays a role in this phenomenon. Here, presenilin 2 (PSEN2) assemblies, unlike those of PSEN1, more prominently affect intracellular Aβ production. Ongoing experiments also imply that PSEN2 expression is under control of PSEN1, suggesting an intriguing molecular crosstalk that could keep the levels of intracellular Aβ in check. Thus, factors that distort the subcellular localization of PSEN2-complexes and/or expression may affect the internal Aβ pool. In this project we aim to: identify key regulators involved in PSEN1 control of PSEN2 levels andtest if these are influenced by familial AD mutations.Furthermore, we will test if PSEN2 localization/levels are affected by altered expression of late onset AD risk genes. This knowledge will be tested in engineered differentiated neurons on lysosome function in turnover and degradation. These complementary approaches may provide further insights into mechanisms that underlie intracellular Aβ pile up and deepen our understanding of processes that govern early stages of AD." "Role of Presenilin2 deficiency and familial Alzheimer's disease mutants in intracellular Abeta accumulation and Alzheimer's disease pathology" "Wim Annaert" "Laboratory of Membrane Trafficking (VIB-KU Leuven)" "Alzheimer’s disease (AD) is characterized by the progressive build-up of amyloid-beta (AB) in plaques. gamma-Secretase processing releases AB from the amyloid precursor protein and comes in different flavours because of the existence of two presenilins and APH1 isoforms. Distinct complexes generate slightly different AB profiles and familial AD linked mutations in PSENs shift the production to longer AB species which aggregate more easily. PSEN1/gamma-secretase is broadly distributed in neurons, whereas PSEN2/gamma-secretase is restricted to late endosomes/lysosomes where it majorly produces the pathological relevant intracellular AB pool. Unexpectedly, PSEN2 deficiency results in higher AB production and increased plaque load in a transgenic AD model pointing to a potential protective role of PSEN2 in AD pathology. I postulate that in normal, healthy conditions, part of APP is processed via PSEN2/gamma-secretase providing a clearance pathway for AB accumulation as long as lysosomes are intact. In PSEN2 deficiency, all APP is processed through PSEN1/gamma-secretase resulting in increased AB secretion and plaque formation. We further predict that in case of FAD-PSEN2 mutations, intracellular toxic AB is strongly promoted leading to its aggregation and ultimately lysosomal dysfunction/damage. To test this hypothesis I will develop new PSEN2-targeted AD models and evaluate in vivo, and including cellular models derived from these models, AD pathology, AB profiles and lysosomal function" "Unraveling the effect of caloric restriction on gene expression in the choroid plexus and correlation with extracellular vesicle production and cognition in mouse models of age-related Alzheimer’ disease" "Claude Libert" "Department of Biomedical molecular biology" "Caloric restriction is the reduction of energy intake without causing undernutrition and combined with normal intake of vitamins, minerals and essential biomolecules. Dietary interventions such as caloric restriction have shown to slow down the aging process, benefit general health and improve memory in Alzheimer’ disease. Our research group conducted extensive study on the choroid plexus cells, an important structure that forms a barrier between the blood and cerebrospinal fluid in the brain. Several choroid plexus related processes are severely affected during healthy aging and are aggravated in Alzheimer’ disease. However caloric restriction seems to have beneficial effects namely a reduction in inflammation, extracellular vesicle release into the CSF and amelioration of the observed memory decline in Alzheimer’ disease mouse models. This research projects aims at investigating how caloric restriction can affect the different choroid plexus epithelium cell processes in Alzheimer’ disease mouse models. To do so, we will study the transcriptome of mice on a calorie restricted diet compared to ad libitum fed mice. In addition, we will investigate the possible protective effect of caloric restriction on short and long term memory in different Alzheimer’ disease mouse models by performing behavioral tests. In summary this project will give novel insights into the mechanisms involved in the age-related disease of Alzheimer’ disease." "High resolution examination of the topological and cell-type specific expression differences of an Alzheimer risk gene." "Kristel Sleegers" "VIB CMN - Genetics of Alzheimer’s Disease" "The identification of genetic risk variants in the GWAS-identified Alzheimer risk gene ABCA7 has been remarkably fruitful, with identification of >50 premature termination codon (PTC) variants, as well as a pathogenic variable number of tandem repeats (VNTR) expansion. While both types of risk variants are predicted to lead to a loss of function, interpretation of the effect of these alleles is challenging, due to a complex splicing pattern and poor correlation between transcript and protein levels, and lack of knowledge of the cell types and tissues in which ABCA7 variants exert their effect. We will combine long-read sequencing and spatial RNA and protein profiling on brain regions and patient-derived cell types to enhance insights of the cellular patterns of ABCA7 expression and splicing in relation to AD. A better understanding of the mode of action of ABCA7 risk alleles will in the long run benefit a significant portion of those at risk of AD, whether through improved risk prediction or targeted intervention. At the shorter term, identification of the cell type(s) in which ABCA7 exerts its risk increasing effects and better insight in the link between transcript and protein expression will inform downstream in vitro modeling and deliver targets for therapy development. Identification of a biomarker for penetrance of ABCA7 risk alleles will benefit risk prediction in research as well as in a clinical setting." "Biomarker based adaptive development in Alzheimer disease." "Kris Dierickx" "Interfaculty Centre for Biomedical Ethics and Law" "Today, more than 46 million people worldwide are living with dementia (Wimo et al., 2013). This number will almost double every 20 years, with an estimated 74 million in 2030 and 131 million in 2050. Dementia refers to the decline of neuropsychological function, affecting one or more cognitive domains including memory, judgement, language, behavior, etc., whereby Alzheimer’s Disease (AD) is the most common type of dementia (Dubroff et al., 2015). Continued growth in the population of patients with AD will translate into an increasing economic burden. The World Alzheimer Report of 2015 indicates how the global costs of dementia have increased from US dollar 604 billion in 2010 to US dollar 818 billion in 2015 (Wimo et al., 2013). This financial burden affects patients, their family members and society (Dubroff et al., 2015). Despite the continued growth, it is estimated that only half of all cases are diagnosed due to the difficulty of recognizing first symptoms (Wimo et al., 2013 and Dubroff et al., 2015). Resulting in late application of therapy, which is currently limited to symptomatic relief. To deduce the previous mentioned impact, multiple stakeholders (clinicians, researchers, pharmaceutical companies, etc.) are asking party for tools that can help to provide an earlier and accurate clinical diagnosis. In this way, biological markers (biomarkers) are useful tools to identify the presence of a disease and to monitor disease progression better compared to the current diagnostic tools. From 2013 on, several Amyloid markers have been approved by, for example, the Food and Drug Administration (FDA) for clinical use. This approval has led researchers to the question whether or not the current policy of non-disclosure of individual research results in the research setting ought to be changed. However, several ethical questions occur: Is an early diagnosis always better? What are the pitfalls when using biomarkers in clinical and research setting? Does knowledge about your early diagnosis or test result always equal power?In this PhD-project, our main focus is twofold: First of all, by mapping and clustering the ethical challenges in a clinical biomarker-based diagnosis of the early phase (MCI due to AD / pAD) of Alzheimer Disease. Secondly, by exploring and investigating the ethical challenges regarding the return of individual research result in the research context.This project consists of 3 phases: In the first phase, a literature study about the current ethical literature on this topic. The second step consists of qualitative empirical research by conducting interviews with MCI patients as part of a clinical trial and focus group interviews with multiple stakeholders: researchers, clinicians, family members and so on. The third and concluding step upholds a normative ethical reflection.  " "Biomarker based adaptive development in Alzheimer (BioAdaptAD)." "Sebastiaan Engelborghs" "Molecular Imaging, Pathology, Radiotherapy & Oncology (MIPRO), Neurochemistry and behaviour" "The general objectives of this project are to develop a BACE inhibitor for disease modification in Alzheimer's disease and to explore the development in an earlier prodromal Alzheimer's disease population. From a drug development perspective, this will involve multiple adaptation steps and the intensive use of biomarkers." "Natural Language Processing analysis of connected speech in Alzheimer disease and related disorders" "Rik Vandenberghe" "Laboratory for Cognitive Neurology" "Language and speech are fundamental for communication between people. Language and speech skills are determined by the extent to which we see and manifest ourselves towards our neighbors and how we participate in society. Studies of well-known individuals who have died of Alzheimer's disease, such as Ronald Reagan or Gerard Reve, have shown that Alzheimer's has altered changes in their lyrics and speeches even before the disease symptoms and diagnosis can be established. In this study, we use the latest language and speech analysis techniques to investigate, in a large group of cognitively normal study participants, computational methods based on language and speech analysis that can distinguish early onset Alzheimer's disease in the brain. We also investigate how these task and speech changes relate to the nerve cell loss and spread of the pathological tau protein.  " "Aβ-Tau cascade promotes oxidative stress and genomic damage that drives neuronal cell loss: DNA repair mechanisms as therapeutic targets in Alzheimer disease" "David WILSON" Neurosciences "Accumulating evidence indicates that combinatorial strategies targeting pathways downstream of Aꞵ and Tau will be required to effectively halt the Alzheimer disease (AD) process. Here, we will investigate DNA repair mechanisms downstream of the Aꞵ-Tau cascade as critical mediators of neurodegeneration. We will determine the importance of aging hallmarks and DNA repair systems in AD etiology to design novel therapeutic approaches to effectively halt the disease." "Translating individual Alzheimer genetic risk into disease phenotypes (TRIAGE)." "Bart De Strooper" "Laboratory for the Research of Neurodegenerative Diseases (VIB-KU Leuven), Laboratory for Cognitive Neurology, UZ Leuven, Universitair Medisch Centrum Utrecht, Cardiff University" "The central hypothesis of TRIAGE is that individual genetic make-up largely accounts fot hte heterogeneity of AD clinical presentation, and that the PRS can be directly translated into specific cellular and molecular pathways that trigger and drive the diseases. Our aims are:To build a map of AD clinical manifestations as a function of the PRS;To identify the elements responsible for AD pathology in representative individuals across the map  by using innovative disease models focussing on microglial responses;To establish a preclinical therapeutic exploration platform that can be directly linked to the PRS;To generate a roadmap forwards personalized medicine to AD."