Janet Van Eersel - Academia.edu (original) (raw)

Papers by Janet Van Eersel

Representative images of AT8 labelling (red) for hyperphosphorylated tau within the (A-C) dorsola... more Representative images of AT8 labelling (red) for hyperphosphorylated tau within the (A-C) dorsolateral protruberance of the medial cerebellar nucleus, (D-F) motor nucleus of the trigeminal nerve (V) and (G-I) motor nucleus of the facial nerve (VII). Nuclei were labelled with bisbenzimide (blue). P -Purkinje cell layer; Gr -granule cell layer. Scale bar in I applies to all images.

Neuropathology and applied neurobiology, Jan 12, 2015

Tau becomes hyperphosphorylated in Alzheimer's disease (AD) and frontotemporal lobar degenera... more Tau becomes hyperphosphorylated in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD-tau), resulting in functional deficits of neurons, neurofibrillary tangle (NFT) formation and eventually dementia. Expression of mutant human tau in the brains of transgenic mice has produced different lines that recapitulate various aspects of FTLD-tau and AD. In this study, we characterised the novel P301S mutant tau transgenic mouse line, TAU58/2. Both young and aged TAU58/2 mice underwent extensive motor testing, after which brain tissue was analysed with immunohistochemistry, silver staining, electron microscopy and Western blotting. Tissue from various FTLD subtypes and AD patients was also analysed for comparison. TAU58/2 mice presented with early-onset motor deficits, which became more pronounced with age. Throughout the brains of these mice, tau was progressively hyperphosphorylated resulting in increased NFT formation with age. In addition, frequent axonal swellings ...

Proceedings of the National Academy of Sciences of the United States of America, 2008

Frontotemporal dementia (FTD) is characterized by cognitive and behavioral changes and, in a sign... more Frontotemporal dementia (FTD) is characterized by cognitive and behavioral changes and, in a significant subset of patients, Parkinsonism. Histopathologically, FTD frequently presents with taucontaining lesions, which in familial cases result from mutations in the MAPT gene encoding tau. Here we present a novel transgenic mouse strain (K3) that expresses human tau carrying the FTD mutation K369I. K3 mice develop a progressive histopathology that is reminiscent of that in human FTD with the K369I mutation. In addition, K3 mice show early-onset memory impairment and amyotrophy in the absence of overt neurodegeneration. Different from our previously generated tau transgenic strains, the K3 mice express the transgene in the substantia nigra (SN) and show an early-onset motor phenotype that reproduces Parkinsonism with tremor, bradykinesia, abnormal gait, and postural instability. Interestingly, motor performance of young, but not old, K3 mice improves upon L-dopa treatment, which bears similarities to Parkinsonism in FTD. The early-onset symptoms in the K3 mice are mechanistically related to selectively impaired anterograde axonal transport of distinct cargos, which precedes the loss of dopaminergic SN neurons that occurs in aged mice. The impaired axonal transport in SN neurons affects, among others, vesicles containing the dopamine-synthesizing enzyme tyrosine hydroxylase. Distinct modes of transport are also impaired in sciatic nerves, which may explain amyotrophy. Together, the K3 mice are a unique model of FTD-associated Parkinsonism, with pathomechanistic implications for the human pathologic process.

PLoS ONE, 2011

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterize... more Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by intraneuronal deposition of the nuclear TAR DNA-binding protein 43 (TDP-43) caused by unknown mechanisms. Here, we studied TDP-43 in primary neurons under different stress conditions and found that only proteasome inhibition by MG-132 or lactacystin could induce significant cytoplasmic accumulation of TDP-43, a histopathological hallmark in disease. This cytoplasmic accumulation was accompanied by phosphorylation, ubiquitination and aggregation of TDP-43, recapitulating major features of disease. Proteasome inhibition produced similar effects in both hippocampal and cortical neurons, as well as in immortalized motor neurons. To determine the contribution of TDP-43 to cell death, we reduced TDP-43 expression using small interfering RNA (siRNA), and found that reduced levels of TDP-43 dose-dependently rendered neurons more vulnerable to MG-132. Taken together, our data suggests a role for the proteasome in subcellular localization of TDP-43, and possibly in disease.

Journal of Neural Transmission, 2009

Frontotemporal lobar degeneration (FTLD) is a common cause of presenile dementia characterised by... more Frontotemporal lobar degeneration (FTLD) is a common cause of presenile dementia characterised by behavioural and language disturbances. Pick's disease (PiD) is a subtype of FTLD, which presents with intraneuronal inclusions consisting of hyperphosphorylated tau protein aggregates. Although Alzheimer's disease (AD) is also characterised by tau lesions, these are both histologically and biochemically distinct from the tau aggregates found in PiD. What determines the distinct characteristics of these tau lesions is unknown. As phosphorylated, soluble tau has been suggested to be the precursor of tau aggregates, we compared both the level and phosphorylation profile of tau in tissue extracts of AD and PiD brains to determine whether the differences in the tau lesions are reflected by differences in soluble tau. Levels of soluble tau were decreased in AD but not PiD. In addition, soluble tau was phosphorylated to a greater extent in AD than in PiD and displayed a different phosphorylation profile in the two disorders. Consistently, tau kinases were activated to different degrees in AD compared with PiD. Such differences in solubility and phosphorylation may contribute, at least in part, to the formation of distinct tau deposits, but may also have implications for the clinical differences between AD and PiD.

IUBMB Life, 2011

Both Alzheimer's disease (AD) and almost every second case of frontotemporal lobar degeneration (... more Both Alzheimer's disease (AD) and almost every second case of frontotemporal lobar degeneration (FTLD) are characterized by the deposition of hyperphosphorylated forms of the microtubule-associated protein tau in neurons and/or glia. This unifying pathology led to coining the umbrella term ''tauopathies'' for these conditions. While the deposition of tau ultimately results in the formation of typical histopathological lesions, such as the neurofibrillary tangles (NFTs) in AD, it is now well accepted that tau interferes with normal functions in neurons already before its deposition. Together with the identification of pathogenic mutations in the tau-encoding gene MAPT in FTLD and evidence from a rising number of in vivo animal models a central role of tau in neurodegeneration has emerged. Here, we review the role of pathological tau in axonal transport, mitochondrial respiration, and in mediating amyloid-b toxicity in AD. Furthermore, we review recent findings regarding the spreading of tau pathology throughout the brain as disease progresses.

Cell, 2010

Alzheimer's disease (AD) is characterized by amyloid-b (Ab) and tau deposition in brain. It has e... more Alzheimer's disease (AD) is characterized by amyloid-b (Ab) and tau deposition in brain. It has emerged that Ab toxicity is tau dependent, although mechanistically this link remains unclear. Here, we show that tau, known as axonal protein, has a dendritic function in postsynaptic targeting of the Src kinase Fyn, a substrate of which is the NMDA receptor (NR). Missorting of tau in transgenic mice expressing truncated tau (Dtau) and absence of tau in tau À/À mice both disrupt postsynaptic targeting of Fyn. This uncouples NR-mediated excitotoxicity and hence mitigates Ab toxicity. Dtau expression and tau deficiency prevent memory deficits and improve survival in Ab-forming APP23 mice, a model of AD. These deficits are also fully rescued with a peptide that uncouples the Fyn-mediated interaction of NR and PSD-95 in vivo. Our findings suggest that this dendritic role of tau confers Ab toxicity at the postsynapse with direct implications for pathogenesis and treatment of AD.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2010

Many proteins that are implicated in human disease are posttranslationally modified. This include... more Many proteins that are implicated in human disease are posttranslationally modified. This includes the microtubule-associated protein tau that is deposited in a hyperphosphorylated form in brains of Alzheimer's disease patients. The focus of this review article is on the physiological and pathological phosphorylation of tau, the relevance of aberrant phosphorylation for disease, the role of kinases and phosphatases in this process, its modeling in transgenic mice, flies and worms, and implications of phosphorylation for therapeutic intervention. 2 A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT with ubiquitin-immunoreactive lesions) or FTDU-17, tau-negative, ubiquitin-positive lesions are prominent. In these patients, mutations were found in the PGRN gene encoding progranulin, a growth factor involved in multiple physiological and pathological processes including tumorigenesis [13, 14]. It was found that the TAR DNA-binding protein of 43 kDa (TDP-43) is a primary constituent of the ubiquitinpositive inclusions in FTLD-U and amyotrophic lateral sclerosis [15]. Under pathological conditions, TDP-43 is, similar to tau, hyperphosphorylated, ubiquitinated, and carboxyterminally truncated [16]. Serine-and threonine-directed phosphorylation of tau Of all post-translational modifications, protein phosphorylation in general receives particular attention as it is an important cellular regulatory mechanism [6]. It determines enzymatic activity, protein stability, folding properties including protein aggregation, binding of other bio-molecules and subcellular localization. Phosphorylation occurs mainly on serine, threonine and tyrosine residues, although proteins can be phosphorylated also on histidine, lysine and arginine residues. Phosphorylation depends on a balanced interplay between kinases and phosphatases that is disturbed under pathological conditions. Phosphorylation can also be affected by O-glycosylation since some serine and threonine residues either being Oglycosylated or phosphorylated [17-20].

Alzheimer's & Dementia, 2011

vitro, BQCA increased carbachol potency approx. 90-fold at 10ÂmM (n ¼ 6). In vivo, a maximal brai... more vitro, BQCA increased carbachol potency approx. 90-fold at 10ÂmM (n ¼ 6). In vivo, a maximal brain level of 270 nM was observed 40 min after i.p. administration at 10 mg/kg. Based on in vitro experiments, at level BQCA should produce about 3-fold increase of the agonist potency; it reduced a scopolamine-induced hyper locomotion. Further, BQCA reversed a deficit observed in the two models of memory impairment. Moreover, BQCA showed no side effect at 10 mg/kg and above in spontaneous locomotion as well as in the salivation test. Conclusions: Altogether, these data suggest that the M1 PAM BQCA may be of interest for the treatment of memory deficits observed in Alzheimer's disease.

Alzheimer's & Dementia, 2010

amyloid is being deposited in association cortex very early, usually several years before onset o... more amyloid is being deposited in association cortex very early, usually several years before onset of clinical symptoms. Atrophy, predominantly of mesial temporal areas, and changes of white matter tracts are associated with onset of significant memory problems. Progressive dysfunction of cortical networks is then seen in FDG PET and fMRI studies, typically a few years before onset of dementia. Transmitter and receptor imaging by PET and SPECT relates cognitive impairment to specific neurotransmitter systems. The influence of age-at-onset, education, vascular changes, genetic factors and microglial activation is being studied, and imaging techniques are being evaluated as biomarkers for clinical trials aiming at prevention of dementia and reduction of disease progression. Conclusions: Molecular imaging confirms very early deposition of amyloid at a presymptomatic stage of AD, while further studies are underway to identify additional factors influencing progression to dementia. THURSDAY, JULY 15, 2010 SYMPOSIUM S5-01 ANIMAL AND CELLULAR MODELS

Proceedings of the National Academy of Sciences, 2010

Alzheimer's disease (AD) brains are characterized by amyloidβ-containing plaques and hyperphospho... more Alzheimer's disease (AD) brains are characterized by amyloidβ-containing plaques and hyperphosphorylated tau-containing neurofibrillary tangles (NFTs); however, in frontotemporal dementia, the tau pathology manifests in the absence of overt amyloid-β plaques. Therapeutic strategies so far have primarily been targeting amyloid-β, although those targeting tau are only slowly beginning to emerge. Here, we identify sodium selenate as a compound that reduces tau phosphorylation both in vitro and in vivo. Importantly, chronic oral treatment of two independent tau transgenic mouse strains with NFT pathology, P301L mutant pR5 and K369I mutant K3 mice, reduces tau hyperphosphorylation and completely abrogates NFT formation. Furthermore, treatment improves contextual memory and motor performance, and prevents neurodegeneration. As hyperphosphorylation of tau precedes NFT formation, the effect of selenate on tau phosphorylation was assessed in more detail, a process regulated by both kinases and phosphatases. A major phosphatase implicated in tau dephosphorylation is the serine/threonine-specific protein phosphatase 2A (PP2A) that is reduced in both levels and activity in the AD brain. We found that selenate stabilizes PP2A-tau complexes. Moreover, there was an absence of therapeutic effects in sodium selenate-treated tau transgenic mice that coexpress a dominant-negative mutant form of PP2A, suggesting a mediating role for PP2A. Taken together, sodium selenate mitigates tau pathology in several AD models, making it a promising lead compound for tau-targeted treatments of AD and related dementias. frontotemporal lobar degeneration | protein phosphatase 2A | neurofibrillary tangle | transgenic | treatment