Research Debby Van Dam

Abstract

The association between hearing impairment and dementia has emerged as a major public health challenge and has triggered increasing interest with significant opportunities for earlier diagnosis, treatment and prevention. Hearing loss appears as a risk factor for cognitive impairment, and has been identified as a potential modifiable age-related condition linked to dementia. Midlife hearing loss, if eliminated, might decrease the risk of dementia in the general population. Few studies so far have examined the relationship between hearing loss and the molecular changes in the brain, and more specifically in the hippocampus, that lead to cognitive dysfunction. This proposal puts forward several innovative research questions to assess the relation between hearing loss, cognitive decline and dementia. Four hypotheses on the causal relationship between peripheral hearing loss and cognitive decline have been proposed. This project considers two of these hypotheses to be tested in relevant mouse models which will allow a direct appraisal of the impact of hearing loss on the onset and time course of cognitive decline, as well as underlying pathophysiological mechanisms. Workpackage 1 explores the "cognitive load on perception" hypothesis by evaluating whether tau pathology induces auditory dysfunction independently of sensory deprivation. Utilizing a validated mouse model of tauopathy, auditory function will be correlated with cognitive parameters. Notably, correction of a single nucleotide variant associated with sensorineural hearing loss will enable a comprehensive study of auditory function. Additionally, the role of cadherin 23 in cognitive decline will be elucidated. Workpackage 2 assesses the "sensory deprivation" hypothesis and investigates the impact of sensory deprivation induced by noise trauma on cognitive decline in wild-type mice. By differentiating between auditory and non-auditory effects of noise trauma, the study aims to uncover the downstream pathophysiology of noise-induced memory loss. Specifically, the involvement of cochlin expression in the hippocampus will be examined. This project aims to unravel the molecular and cellular mechanisms underlying cognitive decline induced by inner ear dysfunction. Focus will be on neuroinflammation, oxidative stress pathways, and their impact on hippocampal neurogenesis. Microglial alterations and related neuroinflammatory processes will be studied as potential links between inner ear dysfunction, dysfunctional neurogenesis, and cognitive decline. Recognizing sexual dimorphism in auditory physiology and susceptibility to age-related hearing loss, this objective emphasizes the inclusion of both male and female subjects to capture sex-specific associations accurately. This study aims to provide a comprehensive understanding of the complex interplay between hearing loss, cognitive decline, and tauopathy, offering insights into potential therapeutic interventions and preventive strategies for age-related cognitive disorders.

Researcher(s)

• Promoter: Van Dam Debby
• Fellow: Kachar Hanane

Research team(s)

• Experimental Neurobiology Unit (ENU)

Project type(s)

• Research Project

Abstract

Hearing loss is the most frequently reported sensory deficit and affects 1.57 billion people worldwide. It has a significant impact on quality of life. Studies have identified a significant correlation between hearing status and cognitive abilities. Deafness Autosomal Dominant 9 (DFNA9) is a dominant hereditary disorder characterized by a progressive sensorineural hearing loss (SNHL) associated with bilateral vestibulopathy (BV). In this project, the applicant will evaluate hearing, vestibular and cognitive function in (pre-)symptomatic DFNA9 patients and in genetically humanized DFNA9 mice. Based on the statistical analysis of baseline (cross-sectional) data already gathered, the applicant hypothesizes that DFNA9 patients are at significant risk for incident cognitive decline. This application presents a novel approach to identify pathophysiological mechanisms of SNHL, BV and cognitive decline in a genetically engineered mouse model designed to mimic DFNA9 in humans. This model is unique in the field of hearing research and will allow us to investigate the therapeutic potential of any gene editing intervention intended for human use beyond the scope of this application. The expected outcome is important to society because it may identify DFNA9 patients at risk for cognitive decline. Subsequently, it will provide data from a genetically humanized mouse model essential to translate findings from fundamental research to clinically meaningful knowledge and clinical trials.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Van Dam Debby
• Fellow: Gommeren Hanne

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

GPCR targets are considered highly "druggable" and a growing interest in GPCRs forming hetero- or homodimers as possible new pharmacological targets in a variety of diseases, including AD and related dementias, has been expressed. The translation of GPCR heterodimers and mosaics to pharmaceutical drug discovery and development is however in its infancy and hampered by the lack of appropriate tools to study these bioconjugates, as well as insufficient understanding of which interactions are important and (patho)physiologically relevant. This project will provide a systematic screening of GPCR expression and subcellular localisation in human brain tissue, as well as in a valid amyloidosis mouse model. Latter model will be applied to provide the very first proof-of-concept that targeting an AD-relevant GPCR heterodimer with a bivalent ligand may provide a novel therapeutic approach that could cause a major shift in AD treatment.

Researcher(s)

• Promoter: De Deyn Peter
• Co-promoter: Van Dam Debby

Research team(s)

Project type(s)

• Research Project

Abstract

Alzheimer's disease (AD) and related dementias are degenerative and irreversible brain illnesses characterized by memory loss, behavioral and psychological signs and symptoms of dementia (BPSD), and an (over)activated neuroimmune response. Interestingly, people with Down syndrome (DS), a congenital disorder, face accelerated aging and are at high risk to develop AD over time; 50- 70% of the DS individuals develop AD. Earlier AD diagnosis and/or prediction of conversion to AD is essential for adaptive caretaking and adequate treatment interventions. BPSD in AD patients are diagnosed using validated rating scales. However, no BPSD scales are available for DS. Therefore, our first aim is to validate and longitudinally apply our recently developed BPSD scale specifically adapted for DS in cohorts of DS patients with and without dementia. Concentration changes in biogenic amines, i.e. neurotransmitters and their metabolites, have been associated with BPSD. We previously discovered that the serum concentration of the monoaminergic neurotransmitter metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) can predict the development of AD in DS. The current project aims to investigate the biological functionality of the monoaminergic neurotransmitter system in human brain, blood and CSF samples. We will also study in detail how brain pathology typical for AD, develops in DS, whether locus coeruleus pathology is observed and how these link to neurotransmitter changes and patients' symptoms.

Researcher(s)

• Promoter: De Deyn Peter
• Co-promoter: Van Dam Debby
• Co-promoter: Vermeiren Yannick

Research team(s)

• Experimental Neurobiology Unit (ENU)

Project type(s)

• Research Project

Abstract

RNA interference-based studies in C. elegans indicated that tryptophan 2,3-dioxygenase (TDO) depletion strongly suppressed proteotoxicity of several aggregation-prone proteins independently of kynurenine metabolites, and moreover positively affected life span of the nematodes. Therefore, we propose that TDO functions as a general regulator of protein toxicity, and hypothesize that increased TDO expression in the brain contributes to the pathophysiology of Alzheimer's disease in particular, and neurodegenerative diseases in general. Interfering with TDO activity might offer novel therapeutic avenues for treating or preventing age-related neurodegenerative diseases. We want to determine whether inhibition of tryptophan degrading pathways reduces age-dependent cognitive decline and behavioural alterations, as well as CNS amyloid deposition in a relevant mouse model for Alzheimer's disease. Genetic depletion of TDO will be accomplished by crossing the APP23 amyloidosis mouse model with a TDO-knockout mouse. The four genotypes of interest are: TDO knockout APP23 mice, TDO knockout (wild-type) mice, TDO-expressing APP23 and wild-type control mice. TDO and its functional homologue indoleamine 2,3-dioxygenase are the first and rate-limiting enzymes in the evolutionary conserved kynurenine pathway. Since growing evidence implicates kynurenine pathway metabolites in the development and progression of Alzheimer's disease, kynurenine pathway metabolites will be determined in CSF, serum and brain tissue of the different genotypes.

Researcher(s)

• Promoter: Van Dam Debby

Research team(s)

Project type(s)

• Research Project

Abstract

Down syndrome (DS), or trisomy 21, is the most common genetic cause of intellectual disability in humans. In addition, 50-70% of the DS individuals develops dementia due to AD before the age of 70. Studying mechanisms in DS does not only contribute to unravelling the pathophysiology in DS, but may also substantially aid to the understanding of AD. Predicting the progression of AD in DS is a major challenge in clinical practice and essential for adaptive caretaking and therapeutic interventions. We hypothesize that accurate recognition of behavioural and psychological symptoms of dementia (BPSD) may improve early identification of those at risk, and provide a non-invasive way to monitor the course to dementia. Elucidating the underlying neurobiological mechanisms further aids novel target identification for goal-directed drug development. While cognitive decline in AD cannot be prevented, specific behavioural symptoms can be reduced, thus improving the quality of life. BPSD in AD patients are diagnosed using validated questionnaires, but unfortunately, no BPSD scales are available for DS. Concentration changes in monoaminergic systems have been associated with BPSD (for example in AD). To that end, we previously quatified the levels of eight biogenic amines and their metabolites in serum of DS subjects with AD, without AD and a non-demented group that converted to AD over time. Our observations indicate that serum MHPG levels might serve a predictive biomarker for conversion to AD in DS. The major aims are therefore to (1) develop a scale for BPSD in DS, which takes DS-specific circumstances into account, (2) validate our previously reported findings on altered serum concentrations of monoaminergic neurotransmitters in relation to the status of dementia and behavioural correlates in DS, and, (3) unravel the central cause(s) of the altered monoaminergic concentrations, and MHPG in particular, in selected post mortem DS brain regions (with/without AD).

Researcher(s)

• Promoter: De Deyn Peter
• Co-promoter: Van Dam Debby

Research team(s)

Project type(s)

• Research Project

Abstract

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: De Deyn Peter
• Co-promoter: Van Dam Debby

Research team(s)

Project type(s)

• Research Project

Abstract

The general objective is to obtain insight in the contribution and working mechanism of two vital processes in the brain: 1) neuroprotection and 2) 17β-estradiol (E2) induced neuroplasticity. As we aim to focus on different expression patterns of Ngb both in vitro and in vivo, the first objective is to improve valid Ngb overexpressing and knock-out (KO) systems.

Researcher(s)

• Promoter: Dewilde Sylvia
• Co-promoter: Ponsaerts Peter
• Co-promoter: Van Dam Debby
• Co-promoter: Van Der Linden Annemie
• Fellow: Luyckx Evi

Research team(s)

Project type(s)

• Research Project

Abstract

We aim to establish an integrated network to identify genes and proteins involved in neurodegenerative disorders, determine their biological functions, establish their role in the pathophysiological processes, identify modifiers of the function by genetic screens, The network meets the prerequisites for such a project: frontline research in functional genomics related to human health, creating synergies with and between research efforts, teaming up with clinical groups through translational research for providing novel avenues for diagnosis, prevention, treatment and providing training and mobility to improve the skills of our young researchers.

Researcher(s)

• Promoter: De Deyn Peter
• Co-promoter: Cras Patrick
• Co-promoter: Engelborghs Sebastiaan
• Co-promoter: Van Dam Debby

Research team(s)

Project type(s)

• Research Project

Abstract

Alzheimer's disease (AD) is the most frequent form of neurodegenerative disease resulting in progressive loss of memory and cognitive abilities. AD is vastly becoming a major medical and social-economical problem in our ageing society. In Europe alone, approximately 7 million people suffer from AD. Despite intense research, pathophysiological mechanisms underlying AD and related disorders are still insufficiently documented. Valid animal models are essential in research ensuing elucidation of human disease processes and testing of potential therapeutic strategies. The valid APP23 transgenic mouse model will be used to further study underlying pathophysiological mechanisms related to soluble aggregates of the amyloid-beta peptide and reactivation of the cell cycle in neurons, with presumed effects at the neurochemical, electrophysiological, morphological and behavioural level. In addition, a model for vascular dementia will be developed by crossing APP23 mice with atherogenic ApoE knockout mice. Based on parallel genetic and environmental risk factors, pathophysiological aspects, and response to therapeutic interventions, it is assumed that convergent disease processes are the basis of AD and atherosclerosis. Behavioural, biochemical and pathological assessments will shed more light onto the link between AD and atherosclerosis, as well as the role of the amyloid precursor protein in atherosclerosis.

Researcher(s)

• Promoter: De Deyn Peter
• Fellow: Van Dam Debby

Research team(s)

Project type(s)

• Research Project

Abstract

Besides being pivotal Alzheimer's disease proces, amyloid precursor protein is presumed to play a crucial rol in atherosclerosis as well. The link between both disorders will be studied in a cross model based on the APP23 transgenic amyloidosis Alzheimer's model and the atherosclerosis-prone ApoE knockout model at the behavioural, biochemical, morphological and histopathological level.

Researcher(s)

• Promoter: Van Dam Debby

Research team(s)

Project type(s)

• Research Project

Abstract

This is a fundamental research project financed by the Research Foundation - Flanders (FWO). The project was subsidized after selection by the FWO-expert panel.

Researcher(s)

• Promoter: De Deyn Peter
• Co-promoter: Van Dam Debby

Research team(s)

Project type(s)

• Research Project

Abstract

This is a fundamental research project financed by the Research Foundation - Flanders (FWO). The project was subsidized after selection by the FWO-expert panel.

Researcher(s)

• Promoter: De Deyn Peter
• Fellow: Van Dam Debby

Research team(s)

Project type(s)

• Research Project

Abstract

A longitudinal, morphometric study of dendrite morphology in the APP23 mouse model for Alzheimer's disease will potentially reveal early stage, and presumably subtle forms of neuronal damage and neurodegeneration. Results will be correlated with age-dependent cognitive decline and amyloid pathology as previously published by our group.

Researcher(s)

• Promoter: Van Dam Debby

Research team(s)

Project type(s)

• Research Project

Abstract

Up to date, no animal model mimics the complete range of histopathological, pathophysiological, cognitive and behavioural alterations, and all models, consequently, are partial models of AD. This research project, therefore, aims at detailed parallel analysis of several pathophysiological AD-related hypotheses in a selection of transgenic mouse models for amyloidosis and tau-related pathology. This approach will lead to reliable and sufficiently substantiated observations and we anticipate in bringing more clarity into the discussion between "baptists" and "tauists".

Researcher(s)

• Promoter: Van Dam Debby

Research team(s)

Project type(s)

• Research Project

Abstract

The link between amyloid ß pathology and clinical symptomatology in Alzheimer's disease is insufficiently convincing. Recently, the amyloid cascade theory was complemented with non-fibrillary soluble Aß oligomeres (Aß-derived diffusible ligands (ADDL), which could form the missing link in the disease process. ADDL and other amyloid precursor protein related molecules will be analyzed in the extensively validated APP23 transgenic mouse model.

Researcher(s)

• Promoter: Van Dam Debby

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: De Deyn Peter
• Fellow: Van Dam Debby

Research team(s)

Project type(s)

• Research Project

Abstract

Dementia (including Alzheimer's disease) (AD) is the fourth most important cause of death in the developed world. Alzheimer's disease is characterized by cognitive impairment and profound behavioural changes leading to death after several years of progressive illness. At the neurochemical level, AD is characterized by a considerable loss of cholinergic neurons leading to a decrease of acetylcholine concentration in the temporal cortex and the cerebrospinal fluid. Other neurotransmitter systems (monoamines, neuropeptides, excitatory and inhibitory amino acids) also exhibit abnormalities. A conclusive diagnosis is only possible after post-mortem brain examination revealing senile plaques, neurofibrillary tangles, dystrophic neurites and neuronal cell loss in specific regions of the brain. Because of the growing group of elderly in our society, AD is a continuously growing medical and socio-economical problem. Unfortunately the exact ethiology of AD still remains unknown. The major goal of AD research is to produce animal models that exhibit pathologic and/or phenotypic features of the humans affected by the disease to learn more about its pathophysiology and to create new treatment opportunities. Mutations in different genes are thought to be related to an increased risk of developping AD. It is one of our goals to validate a mouse model that expresses a mutated 751-amino acid isoform of hAPP under the control of the neuron-specific enolase promotor of the rat. A base substitution on chromosome 21 causes a missense mutation (Val717 ? Ile717) that can be found in patients with familial AD. Behavioural testing examines possible cognitive impairment in an animal model to search for similarities between the deficits in the animals and the cognitive impairment in the human condition. Behavioural testing will be performed on 3, 6 and 12 month old mice. The model expresses low levels of hAPP and does not develop ?-amyloid deposits, and therefore it might be possible to provoke these pathological features. Recent literature states a possible connection between cholesterol, the deposition of A?, and AD. A chronic provocation will be established by putting the mice on a high fat diet (constitution: 15% cacaobutter, 0.5% cholate, 1% cholesterol, 40.5% sucrose, 10% cornstarch, 1% corn oil, and 4.7% cellulose) during 24 weeks. Head injuries cause brain damage leading to physical, cognitive, and behavioural disturbances in humans. In order to further examine this hypothesis a traumatic model of closed head injury for mice will be developed. The effects of these two provocations will be examined at the level of behaviour and cognition, and histopathological examinations will be performed as well. An important motive to generate transgenic (mouse) models is the possibility to test new therapeutic strategies. Prophylactic drugs and drugs used in the symptomatic treatment of human AD patients will be administered to the animals. Whether these drugs can prevent or diminish cognitive deficits should show up during behavioural testing following or during treatment. Since no earlier neurochemical research has been performed, the concentration of neurotransmitters in the brain of the NSE-hAPP751m-model is not known. If behavioural testing of the models reveals cognitive deficits, neurochemical testing will be carried out. Determinations will be performed electrochemically on homogenates of brain tissue after separation of substances by high pressure liquid chromatography (HPLC). The different sections of the research proposal should make it possible for us to validate the different mouse models, and if this turns out possitive these new models could be used for the testing of new pharmaceuticals.

Researcher(s)

• Promoter: De Deyn Peter
• Fellow: Van Dam Debby

Research team(s)

Project type(s)

• Research Project

Abstract

Dementia (including Alzheimer's disease) (AD) is the fourth most important cause of death in the developed world. Alzheimer's disease is characterized by cognitive impairment and profound behavioural changes leading to death after several years of progressive illness. At the neurochemical level, AD is characterized by a considerable loss of cholinergic neurons leading to a decrease of acetylcholine concentration in the temporal cortex and the cerebrospinal fluid. Other neurotransmitter systems (monoamines, neuropeptides, excitatory and inhibitory amino acids) also exhibit abnormalities. A conclusive diagnosis is only possible after post-mortem brain examination revealing senile plaques, neurofibrillary tangles, dystrophic neurites and neuronal cell loss in specific regions of the brain. Because of the growing group of elderly in our society, AD is a continuously growing medical and socio-economical problem. Unfortunately the exact ethiology of AD still remains unknown. The major goal of AD research is to produce animal models that exhibit pathologic and/or phenotypic features of the humans affected by the disease to learn more about its pathophysiology and to create new treatment opportunities. Mutations in different genes are thought to be related to an increased risk of developping AD. It is one of our goals to validate a mouse model that expresses a mutated 751-amino acid isoform of hAPP under the control of the neuron-specific enolase promotor of the rat. A base substitution on chromosome 21 causes a missense mutation (Val717 ? Ile717) that can be found in patients with familial AD. Behavioural testing examines possible cognitive impairment in an animal model to search for similarities between the deficits in the animals and the cognitive impairment in the human condition. Behavioural testing will be performed on 3, 6 and 12 month old mice. The model expresses low levels of hAPP and does not develop ?-amyloid deposits, and therefore it might be possible to provoke these pathological features. Recent literature states a possible connection between cholesterol, the deposition of A?, and AD. A chronic provocation will be established by putting the mice on a high fat diet (constitution: 15% cacaobutter, 0.5% cholate, 1% cholesterol, 40.5% sucrose, 10% cornstarch, 1% corn oil, and 4.7% cellulose) during 24 weeks. Head injuries cause brain damage leading to physical, cognitive, and behavioural disturbances in humans. In order to further examine this hypothesis a traumatic model of closed head injury for mice will be developed. The effects of these two provocations will be examined at the level of behaviour and cognition, and histopathological examinations will be performed as well. An important motive to generate transgenic (mouse) models is the possibility to test new therapeutic strategies. Prophylactic drugs and drugs used in the symptomatic treatment of human AD patients will be administered to the animals. Whether these drugs can prevent or diminish cognitive deficits should show up during behavioural testing following or during treatment. Since no earlier neurochemical research has been performed, the concentration of neurotransmitters in the brain of the NSE-hAPP751m-model is not known. If behavioural testing of the models reveals cognitive deficits, neurochemical testing will be carried out. Determinations will be performed electrochemically on homogenates of brain tissue after separation of substances by high pressure liquid chromatography (HPLC). The different sections of the research proposal should make it possible for us to validate the different mouse models, and if this turns out possitive these new models could be used for the testing of new pharmaceuticals.

Researcher(s)

• Promoter: De Deyn Peter
• Fellow: Van Dam Debby

Research team(s)

Project type(s)

• Research Project