ORCID Profile
0000-0003-0916-248X
Current Organisations
KU Leuven
,
Katholieke Universiteit Leuven
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Publisher: Portland Press Ltd.
Date: 26-07-2010
DOI: 10.1042/BST0380967
Abstract: Tau pathology is characterized by intracellular aggregates of abnormally and hyperphosphorylated tau proteins. It is encountered in many neurodegenerative disorders, but also in aging. These neurodegenerative disorders are referred to as tauopathies. Comparative biochemistry of the tau aggregates shows that they differ in both tau isoform phosphorylation and content, which enables a molecular classification of tauopathies. In conditions of dementia, NFD (neurofibrillary degeneration) severity is correlated to cognitive impairment and is often considered as neuronal death. Using tau animal models, analysis of the kinetics of tau phosphorylation, aggregation and neuronal death in parallel to electrophysiological and behavioural parameters indicates a disconnection between cognition deficits and neuronal cell death. Tau phosphorylation and aggregation are early events followed by cognitive impairment. Neuronal death is not observed before the oldest ages. A sequence of events may be the formation of toxic phosphorylated tau species, their aggregation, the formation of neurofibrillary tangles (from pre-tangles to ghost tangles) and finally neuronal cell death. This sequence will last from 15 to 25 years and one can ask whether the aggregation of toxic phosphorylated tau species is a protection against cell death. Apoptosis takes 24 h, but NFD lasts for 24 years to finally kill the neuron or rather to protect it for more than 20 years. Altogether, these data suggest that NFD is a transient state before neuronal death and that therapeutic interventions are possible at that stage.
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.NLM.2010.12.005
Abstract: We evaluated various forms of hippoc us-dependent learning and memory, and hippoc al synaptic plasticity in THY-Tau22 transgenic mice, a murine tauopathy model that expresses double-mutated 4-repeat human tau, and shows neuropathological tau hyperphosphorylation and aggregation throughout the brain. Focussing on hippoc us, immunohistochemical studies in aged THY-Tau22 mice revealed prominent hyper- and abnormal phosphorylation of tau in CA1 region, and an increase in glial fibrillary acidic protein (GFAP) in hippoc us, but without signs of neuronal loss. These mice displayed spatial, social, and contextual learning and memory defects that could not be reduced to subtle neuromotor disability. The behavioral defects coincided with changes in hippoc al synaptic functioning and plasticity as measured in paired-pulse and novel long-term depression protocols. These results indicate that hippoc al tauopathy without neuronal cell loss can impair neural and behavioral plasticity, and further show that transgenic mice, such as the THY-Tau22 strain, might be useful for preclinical research on tauopathy pathogenesis and possible treatment.
Publisher: Frontiers Media SA
Date: 08-10-2020
Publisher: Oxford University Press (OUP)
Date: 04-04-2017
DOI: 10.1093/BRAIN/AWX052
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.BBR.2012.12.008
Abstract: THY-Tau22 mice constitute an animal model for tau aggregation, a hallmark in Alzheimer's disease (AD) and Tauopathies. Our previous studies have shown learning and memory deficits and changes in synaptic plasticity in the hippoc us in THY-Tau22 mice that are consistent with the learning impairments seen in AD-patients. However, behavioral disturbances are the most important problems in the management of AD and are major determinants of nursing home placement. Thus, we hypothesized that THY-Tau22 mice would demonstrate, in addition to the cognitive impairments, at least some behavioral and psychological signs and symptoms of dementia (BPSD). We found that 12 months old THY-Tau22 mice, relative to wild-type (WT) littermates display increased depression-like and aggressive behavior, co-occurring with disturbances in nocturnal activity. Moreover, these changes were linked to a decreased hippoc al concentration in serotonin, or 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin. Together these data corroborate the usefulness of the model in preclinical evaluations of therapeutic strategies that aim to reverse cognitive defects and alleviate BPSD in the human disease.
Publisher: Springer Science and Business Media LLC
Date: 06-08-2011
DOI: 10.1007/S12031-011-9604-5
Abstract: The accumulation of proteins such as Tau is a hallmark of several neurodegenerative diseases, e.g., frontotemporal dementia (FTD). So far, many mouse models of tauopathies have been generated by the use of mutated or truncated human Tau isoforms in order to enhance the amyloidogenic character of Tau and to mimic pathological processes similar to those in FTD patients. Our inducible mice express the repeat domain of human Tau (Tau(RD)) carrying the FTDP-17 mutation ΔK280 in a "pro-aggregant" and an "anti-aggregant" version. Based on the enhanced tendency of Tau to aggregate, only the "pro-aggregant" Tau(RD) mice develop Tau pathology (hyperphosphorylation, coassembly of human and mouse Tau, synaptic loss, and neuronal degeneration). We have now carried out behavioral and electrophysiological analyses showing that only the pro-aggregant Tau(RD) mice have impaired learning/memory and a distinct loss of LTP. Remarkably, after suppressing the pro-aggregant human Tau(RD), memory and LTP recover, while neuronal loss persists. Aggregates persist as well but change their composition from mixed human/mouse to mouse Tau only. The rescue of cognition and synaptic plasticity is explained by a partial recovery of spine synapses in the hippoc us. These results indicate a tight relationship between the amyloidogenic character of Tau and brain malfunction, and suggest that the cognitive impairment is caused by toxic human Tau(RD) species rather than by mouse Tau aggregates.
Publisher: Cambridge University Press
Date: 26-05-2022
Abstract: Dementia is increasingly being recognised as a public health priority and poses one of the largest challenges we face as a society. At the same time, there is a growing awareness that the quest for a cure for Alzheimer's disease and other causes of dementia needs to be complemented by efforts to improve the lives of people with dementia. To gain a better understanding of dementia and of how to organize dementia care, there is a need to bring together insights from many different disciplines. Filling this knowledge gap, this book provides an integrated view on dementia resulting from extensive discussions between world experts from different fields, including medicine, social psychology, nursing, economics and literary studies. Working towards a development of integrative policies focused on social inclusion and quality of life, Dementia and Society reminds the reader that a better future for persons with dementia is a collective responsibility.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.NLM.2016.01.007
Abstract: Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder, a major subset of which is characterized by the accumulation of abnormal forms of the protein tau, leading to impairments in motor functions as well as language and behavioral alterations. Tau58-2/B mice express human tau with the P301S mutation found in familial forms of FTLD in neurons. By assessing three age cohorts of Tau58-2/B mice in a comprehensive behavioral test battery, we found that the tauopathy animals showed age-dependent signs of impulsivity, decreased social exploration and executive dysfunction. The deficit in executive function was first limited to decreased spatial working memory, but with aging this was extended to impaired instrumental short-term memory. Tau pathology was prominent in brain regions underlying these behaviors. Thus, Tau-58-2/B mice recapitulate neurological deficits of the behavioral variant of frontotemporal dementia (bvFTD), presenting them as a suitable model to test therapeutic interventions for the amelioration of this variant.
Publisher: Springer Science and Business Media LLC
Date: 25-04-2012
Publisher: MyJove Corporation
Date: 25-01-2018
DOI: 10.3791/57029
Publisher: Wiley
Date: 04-02-2017
DOI: 10.1111/ACEL.12565
Publisher: Springer Science and Business Media LLC
Date: 02-12-2014
DOI: 10.1038/MP.2014.151
Abstract: Consumption of caffeine, a non-selective adenosine A2A receptor (A2AR) antagonist, reduces the risk of developing Alzheimer's disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippoc al plasticity, neurotransmitter profile). We found that deleting A2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippoc al long-term depression. These effects were concomitant with a normalization of the hippoc al glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A2A receptors as important molecular targets to consider against AD and Tauopathies.
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.NEUROBIOLAGING.2014.05.005
Abstract: Tau has been implicated in the organization, stabilization, and dynamics of microtubules. In Alzheimer's disease and more than 20 neurologic disorders tau missorting, hyperphosphorylation, and aggregation is a hallmark. They are collectively referred to as tauopathies. Although the impact of human tauopathies on cognitive processes has been explored in transgenic mouse models, the functional consequences of tau deletion on cognition are far less investigated. Here, we subjected tau knock-out (KO) mice to a battery of neurocognitive, behavioral, and electrophysiological tests. Although KO and wild-type mice were indistinguishable in motor abilities, exploratory and anxiety behavior, KO mice showed impaired contextual and cued fear conditioning. In contrast, extensive spatial learning in the water maze resulted in better performance of KO mice during acquisition. In electrophysiological experiments, basal synaptic transmission and paired-pulse facilitation in the hippoc al CA1-region were unchanged. Interestingly, deletion of tau resulted in severe deficits in long-term potentiation but not long-term depression. Our results suggest a role of tau in certain cognitive functions and implicate long-term potentiation as the relevant physiological substrate.
Publisher: Springer Science and Business Media LLC
Date: 24-04-2018
DOI: 10.1038/S41598-018-24741-0
Abstract: Accumulation of amyloid-β plaques and tau contribute to the pathogenesis of Alzheimer’s disease (AD), but it is unclear whether targeting tau pathology by antioxidants independently of amyloid-β causes beneficial effects on memory and neuropsychiatric symptoms. Selenium, an essential antioxidant element reduced in the aging brain, prevents development of neuropathology in AD transgenic mice at early disease stages. The therapeutic potential of selenium for ameliorating or reversing neuropsychiatric and cognitive behavioral symptoms at late AD stages is largely unknown. Here, we evaluated the effects of chronic dietary sodium selenate supplementation for 4 months in female 3xTg-AD mice at 12–14 months of age. Chronic sodium selenate treatment efficiently reversed hippoc al-dependent learning and memory impairments, and behavior- and neuropsychiatric-like symptoms in old female 3xTg-AD mice. Selenium significantly decreased the number of aggregated tau-positive neurons and astrogliosis, without globally affecting amyloid plaques, in the hippoc us of 3xTg-AD mice. These results indicate that selenium treatment reverses AD-like memory and neuropsychiatric symptoms by a mechanism involving reduction of aggregated tau and/or reactive astrocytes but not amyloid pathology. These results suggest that sodium selenate could be part of a combined therapeutic approach for the treatment of memory and neuropsychiatric symptoms in advanced AD stages.
Publisher: American Psychological Association (APA)
Date: 2009
DOI: 10.1037/A0013990
Abstract: The hippoc us (HC) has been suggested to play a role in transitive inference (TI) on an ordered sequence of stimuli. However, it has remained unclear whether HC is involved in the expression of TI, or rather contributes to TI through its role in the acquisition of the sequence of elements (Frank, Rudy, & O'Reilly, 2003). Presently, the authors compared the effects of excitotoxic dorsal HC lesions in C57BL mice that received surgery before or after they were trained to discriminate between pairs of visual stimuli. Performance on a subsequent TI task was worse in mice with pretraining lesions than in those with posttraining lesions, which showed similar performance to shams without lesions. This indicates that HC is not involved in the expression of TI, but may merely help to acquire the underlying representations required for TI.
Publisher: Society for Neuroscience
Date: 16-02-2011
DOI: 10.1523/JNEUROSCI.5245-10.2011
Abstract: This report describes the behavioral and electrophysiological analysis of regulatable transgenic mice expressing mutant repeat domains of human Tau (Tau RD ). Mice were generated to express Tau RD in two forms, differing in their propensity for β-structure and thus in their tendency for aggregation (“pro-aggregant” or “anti-aggregant”) (Mocanu et al., 2008). Only pro-aggregant mice show pronounced changes typical for Tau pathology in Alzheimer's disease (aggregation, missorting, hyperphosphorylation, synaptic and neuronal loss), indicating that the β-propensity and hence the ability to aggregate is a key factor in the disease. We now tested the mice with regard to neuromotor parameters, behavior, learning and memory, and synaptic plasticity and correlated this with histological and biochemical parameters in different stages of switching Tau RD on or off. The mice are normal in neuromotor tests. However, pro-aggregant Tau RD mice are strongly impaired in memory and show pronounced loss of long-term potentiation (LTP), suggesting that Tau aggregation specifically perturbs these brain functions. Remarkably, when the expression of human pro-aggregant Tau RD is switched on for ∼10 months and off for ∼4 months, memory and LTP recover, whereas aggregates decrease moderately and change their composition from mixed human plus mouse Tau to mouse Tau only. Neuronal loss persists, but synapses are partially rescued. This argues that continuous presence of amyloidogenic pro-aggregant Tau RD constitutes the main toxic insult for memory and LTP, rather than the aggregates as such.
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.NBD.2017.07.013
Abstract: Alpha-mannosidosis is a glycoproteinosis caused by deficiency of lysosomal acid alpha-mannosidase (LAMAN), which markedly affects neurons of the central nervous system (CNS), and causes pathognomonic intellectual dysfunction in the clinical condition. Cognitive improvement consequently remains a major therapeutic objective in research on this devastating genetic error. Immune-tolerant LAMAN knockout mice were developed to evaluate the effects of enzyme replacement therapy (ERT) by prolonged administration of recombinant human enzyme. Biochemical evidence suggested that hippoc us may be one of the brain structures that benefits most from long-term ERT. In the present functional study, ERT was initiated in 2-month-old immune-tolerant alpha-mannosidosis mice and continued for 9months. During the course of treatment, mice were trained in the Morris water maze task to assess spatial-cognitive performance, which was related to synaptic plasticity recordings and hippoc al histopathology. Long-term ERT reduced primary substrate storage and neuroinflammation in hippoc us, and improved spatial learning after mid-term (10weeks+) and long-term (30weeks+) treatment. Long-term treatment substantially improved the spatial-cognitive abilities of alpha-mannosidosis mice, whereas the effects of mid-term treatment were more modest. Detailed analyses of spatial memory and spatial-cognitive performance indicated that even prolonged ERT did not restore higher cognitive abilities to the level of healthy mice. However, it did demonstrate marked therapeutic effects that coincided with increased synaptic connectivity, reflected by improvements in hippoc al CA3-CA1 long-term potentiation (LTP), expression of postsynaptic marker PSD-95 as well as postsynaptic density morphology. These experiments indicate that long-term ERT may hold promise, not only for the somatic defects of alpha-mannosidosis, but also to alleviate cognitive impairments of the disorder.
Location: United States of America
Start Date: 2016
End Date: 2016
Funder: Fonds Wetenschappelijk Onderzoek
View Funded ActivityStart Date: 2018
End Date: 2018
Funder: Dana Foundation
View Funded ActivityStart Date: 2018
End Date: 2018
Funder: Fonds Wetenschappelijk Onderzoek
View Funded ActivityStart Date: 2015
End Date: 2015
Funder: Fonds Wetenschappelijk Onderzoek
View Funded ActivityStart Date: 2009
End Date: 2009
Funder: Fonds Wetenschappelijk Onderzoek
View Funded ActivityStart Date: 2014
End Date: 2017
Funder: Fonds Wetenschappelijk Onderzoek
View Funded ActivityStart Date: 2009
End Date: 2014
Funder: Fonds Wetenschappelijk Onderzoek
View Funded Activity