Max Holzer - Academia.edu (original) (raw)
Papers by Max Holzer
Brain, 2019
Using trio exome sequencing, Horn et al. identify de novo gain-of-function mutations in PAK1 in f... more Using trio exome sequencing, Horn et al. identify de novo gain-of-function mutations in PAK1 in four unrelated individuals with intellectual disability, macrocephaly and seizures. PAK1 encodes a p21-activated kinase, which has been implicated in brain development and control of brain size.
PLoS ONE, 2014
Swiprosin-1/EFhd2 (EFhd2) is a cytoskeletal Ca 2+ sensor protein strongly expressed in the brain.... more Swiprosin-1/EFhd2 (EFhd2) is a cytoskeletal Ca 2+ sensor protein strongly expressed in the brain. It has been shown to interact with mutant tau, which can promote neurodegeneration, but nothing is known about the physiological function of EFhd2 in the nervous system. To elucidate this question, we analyzed EFhd2 2/2 /lacZ reporter mice and showed that lacZ was strongly expressed in the cortex, the dentate gyrus, the CA1 and CA2 regions of the hippocampus, the thalamus, and the olfactory bulb. Immunohistochemistry and western blotting confirmed this pattern and revealed expression of EFhd2 during neuronal maturation. In cortical neurons, EFhd2 was detected in neurites marked by MAP2 and co-localized with preand post-synaptic markers. Approximately one third of EFhd2 associated with a biochemically isolated synaptosome preparation. There, EFhd2 was mostly confined to the cytosolic and plasma membrane fractions. Both synaptic endocytosis and exocytosis in primary hippocampal EFhd2 2/2 neurons were unaltered but transport of synaptophysin-GFP containing vesicles was enhanced in EFhd2 2/2 primary hippocampal neurons, and notably, EFhd2 inhibited kinesin mediated microtubule gliding. Therefore, we found that EFhd2 is a neuronal protein that interferes with kinesin-mediated transport.
ChemInform, 2005
Protected mercaptoalkylpyrimidinones: synthesis and test for immunostimulating activity 3-Hydroxy... more Protected mercaptoalkylpyrimidinones: synthesis and test for immunostimulating activity 3-Hydroxyalkyl-pyrimidine 1 reacts with phosphoroxychloride and thioglycolic acid or thiourea to yield pyrimidin-3-ylalkylthioacetic acids 3 or pyrimidin-3-ylalkylthiouroniumsalts 5 respectively. Some of the pyrimidines 3 and 5 showed immunomodulatory activity.
ChemInform, 2004
Background and Objectives Filgotinib (GLPG0634) is a selective inhibitor of Janus kinase 1 (JAK1)... more Background and Objectives Filgotinib (GLPG0634) is a selective inhibitor of Janus kinase 1 (JAK1) currently in development for the treatment of rheumatoid arthritis and Crohn's disease. While less selective JAK inhibitors have shown long-term efficacy in treating inflammatory conditions, this was accompanied by dose-limiting side effects. Here, we describe the pharmacokinetics of filgotinib and its active metabolite in healthy volunteers and the use of pharmacokinetic-pharmacodynamic modeling and simulation to support dose selection for phase IIB in patients with rheumatoid arthritis. Methods Two trials were conducted in healthy male volunteers. In the first trial, filgotinib was administered as single doses from 10 mg up to multiple daily doses of 200 mg. In the second trial, daily doses of 300 and 450 mg for 10 days were evaluated. Non-compartmental analysis was used to determine individual pharmacokinetic parameters for filgotinib and its metabolite. The overall pharmacodynamic activity for the two moieties was assessed in whole blood using interleukin-6-induced phosphorylation of signal-transducer and activator of transcription 1 as a biomarker for JAK1 activity. These data were used to conduct non-linear mixed-effects modeling to investigate a pharmacokinetic/pharmacodynamic relationship. Results Modeling and simulation on the basis of early clinical data suggest that the pharmacokinetics of filgotinib are dose proportional up to 200 mg, in agreement with observed data, and support that both filgotinib and its metabolite contribute to its pharmacodynamic effects. Simulation of biomarker response supports that the maximum pharmacodynamic effect is reached at a daily dose of 200 mg filgotinib. Conclusion Based on these results, a daily dose range up to 200 mg has been selected for phase IIB dose-finding studies in patients with rheumatoid arthritis. Key Points Early clinical studies in healthy volunteers with the first selective Janus kinase 1 inhibitor, filgotinib, showed high exposure to an active metabolite that contributes to its overall pharmacodynamic effects. Dose-dependent pharmacodynamic activity of combined filgotinib and its metabolite was shown in whole blood from healthy volunteers following oral dosing of filgotinib. Pharmacokinetic/pharmacodynamic modeling and simulation show a maximal pharmacodynamic effect is achieved at daily dosing of 200 mg filgotinib, and this dose was selected as the highest in a phase IIB program in patients with rheumatoid arthritis.
Liebigs Annalen der Chemie, 1994
Synthesis of N-Substituted 0x0-and Thioxopyrimidines from 1,2,4-Dithiazolium Salts* 2,4-Diaryl-su... more Synthesis of N-Substituted 0x0-and Thioxopyrimidines from 1,2,4-Dithiazolium Salts* 2,4-Diaryl-substituted 1,3-thiazine-5-carbonitriles 5 , 6, obtained by reaction of 1,2,4-dithiazolium salts 1 with activated cyanoacetates, undergo ring transformations in the presence of primary and secondary amines. Thus, 5 and 6 react with primary amines under mild conditions to give hardly accessible N-3-substituted oxopyrimidine-or thioxopyrimidine-5-carbonitriles 11, 16, with secondary amines to give N-3-unsubstituted pyrimidine derivates 14, 19 and with diamines to give imidazo[ 1,2-c]pyrimidines or pyrimido[ 1,2-c]pyrimidines 23a, b. After alkylation of 1,3-thiazines 6, highly reactive 1,3-thiazinium salts 8 can be isolated.
Molecular Psychiatry
The microtubule-associated protein tau plays a central role in tauopathies such as Alzheimer’s di... more The microtubule-associated protein tau plays a central role in tauopathies such as Alzheimer’s disease (AD). The exact molecular mechanisms underlying tau toxicity are unclear, but aging is irrefutably the biggest risk factor. This raises the question of how cellular senescence affects the function of tau as a microtubule regulator. Here we report that the proportion of tau that is proteolytically cleaved at the caspase-3 site (TauC3) doubles in the hippocampus of senescent mice. TauC3 is also elevated in AD patients. Through quantitative live-cell imaging, we show that TauC3 has a drastically reduced dynamics of its microtubule interaction. Single-molecule tracking of tau confirmed that TauC3 has a longer residence time on axonal microtubules. The reduced dynamics of the TauC3-microtubule interaction correlated with a decreased transport of mitochondria, a reduced processivity of APP-vesicle transport and an induction of region-specific dendritic atrophy in CA1 neurons of the hippo...
Biomolecules, 2022
Tau mutations promote the formation of tau oligomers and filaments, which are neuropathological s... more Tau mutations promote the formation of tau oligomers and filaments, which are neuropathological signs of several tau-associated dementias. Types of neurons in the CNS are spared of tau pathology and are surrounded by a specialized form of extracellular matrix; called perineuronal nets (PNs). Aggrecan, the major PN proteoglycans, is suggested to mediate PNs neuroprotective function by forming an external shield preventing the internalization of misfolded tau. We recently demonstrated a correlation between aggrecan amount and the expression and phosphorylation of tau in a TauP310L-acan mouse model, generated by crossbreeding heterozygous aggrecan mice with a significant reduction of aggrecan and homozygous TauP301L mice. Neurodegenerative processes have been associated with changes of PN structure and protein signature. In this study, we hypothesized that the structure and protein expression of PNs in this TauP310L-acan mouse is regulated by tau. Immunohistochemical and biochemical an...
Einleitung 1 1 EINLEITUNG "Liebe Landsleute, vor kurzem habe ich erfahren, dass ich einer der Mil... more Einleitung 1 1 EINLEITUNG "Liebe Landsleute, vor kurzem habe ich erfahren, dass ich einer der Millionen Amerikaner bin, die an Alzheimer erkrankt sind.[…] Ich beginne nun die Reise, die mich zum Sonnenuntergang meines Lebens führt." [1, 2] Mit diesen Worten verabschiedete sich der an Alzheimer erkrankte Ronald Reagan, am 05.11.1994, von der Amerikanischen Gesellschaft. Der facettenreiche Schauspieler und 40. US-Präsident überlebte den Kampf gegen die progressive, neurodegenerative Krankheit nicht. Wie ihm erging es, laut ALZHEIMER´S DISEASE INTERNATIONAL (ADI), im Jahr 2015 über 47 Millionen Menschen weltweit, die mit einer Demenzerkrankung zu kämpfen hatten-darunter waren 9,9 Millionen Neuerkrankungen. Das bedeutet, dass alle 3,2 Sekunden ein neuer Demenzfall diagnostiziert wird. Das ADI schätzt, dass die Zahl bis 2050 auf 132 Millionen ansteigen wird. [3] In Deutschland leben bis zu 1,2 Millionen Demenzerkrankte. [4] Demenz stellt ein Syndrom mit einem großen Symptompool dar. Mit schleichendem Beginn, geprägt vom Rückgang kognitiver Fähigkeiten, erleben die Betroffenen, anfangs bei vollem Bewusstsein, einen Persönlichtkeitsverlust. Derartige Störungen höherer kortikaler Funktionen sind vorrangig Beeinträchtigungen des Gedächtnisses, der Aufmerksamkeit sowie des Denk-und Urteilsvermögens. [4] Während des progredienten Krankeitsverlaufes sind die Betroffenen nicht mehr in der Lage einfachste Alltagshandlungen ohne Unterstützung zu bewältigen. [5] Gepaart mit Ängsten und Depressionen, entwickeln sich im fortgeschrittenen Stadium vegetative Funktionsstörungen, wie Inkontinenz, das Unvermögen des Kauens, Schluckens und des Atmens. Der so geschwächte Körper bietet viel Angriffsfläche für weitere Komorbiditäten. Nicht selten versterben die Leidtragenden an nicht mehr therapierbaren Infektionen, wie Pneumonien oder Sepsen. Durch soziale Interaktionen können die Betroffenen die ersten Symptome geschickt verschleiern. Treten diese aber in den Vordergrund sind der Zerfall bestimmter Hirnareale und der langsame Rückgang von Nervenzellen schon so weit fortgeschritten, dass das menschliche Gehirn die Fehlfunktion einzelner Abschnitte nicht mehr ausgleichen kann. Ursächlich hierfür sind zum einen neurodegenerative Krankheitsbilder. Hierzu zählen die am häufigsten diagnostizierte Form, die Alzheimer-Demenz (60 bis 70 %), die Lewy-Körperchen-Demenz (15 %) und die Frontotemporale Demenz (5 %). Zum anderen können kleine, kumulierte Infarkte und Läsionen im Gehirn eine Vaskuläre Demenz (10 %) hervorrufen. Fast die Hälfte der Erkrankungen treten als Mischformen auf (Abbildung 1, links, Seite 2). [5] Ihre Differentialdiagnose und Abgrenzung zu anderen neurologischen Erkrankungen ist langwierig und vielschichtig. Für die Diagnosestellung muss die Symptomatik, laut Internationaler statistischer Klassifikation von Krankheiten (ICD-10), mindstestens sechs Monate anhalten. Sie reicht von sozialer, Eigen-, Fremd-, sowie Familienanamnese, über kognitive Tests, wie den Mini Mental Status Test (MMST), den Demenz Detektion Test (DemTect) beziehungsweise den Alzheimer's disease assessment scale cognition-Test (ADAS cog) bis hin zu bildgebenden Verfahren, wie die kraniale Computertomographie (cCT), die kraniale Magnetresonanztomographie (cMRT), Einleitung 2 die Positronen-Emissions-Tomographie (PET) und die Elektroenzephalographie (EEG). Weiterhin können serologische und biochemische Untersuchungen des Blutes sowie die Überprüfung der genetischen Veranlagung hilfreich sein. [4] Eine abschließende Diagnose kann erst post mortem durch eine Gehirnautopsie und histopathologischer Untersuchung erfolgen. Abbildung 1: Ursachen und Prävalenz für Demenzen. Ursachen für Demenzen nach Häufigkeit (links) [6] , Prävalenz für Demenz in Europa nach Altersgruppen, 2013 (rechts) [5]. Demenz ist in der westlichen Welt die vierthäufigste Todesursache nach Herzkreislauf-Erkrankungen, Gewebsneubildungen und zerebrovaskulären Erkrankungen. Dabei ist das Alter der größte Risikofaktor. Die 75-bis 79-Jährigen erkranken viereinhalb Mal häufiger an einer Demenz als ihre zehn Jahre jüngeren Mitmenschen. Die Prävalenzrate steigt von unter einem Prozent, für die 60-bis 65-Jährigen, auf 41 Prozent, für die 90-bis 94-Jährigen (Abbildung 1, rechts). [5] Weiterhin korrelieren Bluthochdruck, Diabetes mellitus, Depressionen im mittleren Alter, soziale Isolation, ein niedriger Bildungsstand sowie ein geringes Einkommen mit dem Risiko an Demenz zu erkranken. [5, 7] Das ADI schätzte die globalen Kosten zur Behandlung und Pflege von Demenzpatienten für das Jahr 2015 auf 818 Milliarden US-Dollar-das entspricht 1,09 Prozent des weltweiten Bruttosozialproduktes-und erwartet einen Anstieg auf bis zu 2000 Milliarden US-Dollar für das Jahr 2030. [3] Alarmierende Zahlen, die die WORLD HEALTH ORGANIZATION (WHO) veranlasst haben mit ihrem GLOBAL ACTION PLAN, von 2017 bis 2025, die Behandlung und die Prävention der Demenz, sowie die soziale Unterstützung und die Menschenrechte der Patienten international zu harmonisieren und außerdem die Forschungskosten um das Zweifache zu erhöhen. [8] Im Folgenden wird speziell auf die Alzheimersche Erkrankung Bezug genommen.
Neuropathology, 2021
Vascular calcification is a common phenomenon in the elderly, predominantly appearing in the basa... more Vascular calcification is a common phenomenon in the elderly, predominantly appearing in the basal ganglia and in the lamina circumvoluta medullaris of the hippocampus. Calcifications are not an inherent feature of Alzheimer's disease. On the other hand, a rare presenile type of dementia with symmetrical Fahr‐type calcifications and numerous neurofibrillary tangles without senile plaques has been described by Kosaka in 1994 and was termed “diffuse neurofibrillary tangles with calcification” (DNTC). We here report a case of Alzheimer's disease with calcifications both in the basal ganglia and in the lamina circumvoluta medullaris of the hippocampus, differing from DNTC by the presence of senile plaques. The calcifications in the hippocampus were not only vascular in nature but also covered amyloid‐β‐ and phosphorylated tau‐positive plaque‐like structures that were linearly arranged along the dentate fascia in the CA1 sector, an unusual finding of pathogenetic interest.
European Journal of Neuroscience, 2020
Selected types of neurons in the central nervous system are associated with a specialized form of... more Selected types of neurons in the central nervous system are associated with a specialized form of extracellular matrix. These so‐called perineuronal nets (PNs) are supramolecular structures surrounding neuronal somata, proximal dendrites and axon initial segments. PNs are involved in the regulation of plasticity and synaptic physiology. In addition, PNs were proposed to carry neuroprotective functions as PN‐ensheathed neurons are mostly spared of tau pathology in brains of Alzheimer patients. Recently, the neuroprotective action of PNs was confirmed experimentally, demonstrating (i) that mainly aggrecan mediates the neuroprotective function of PNs and (ii) that aggrecan seems to generate an external shielding preventing the internalization of pathological forms of tau. In the present study, we aimed at extending these findings and hypothesized that aggrecan further provides an intracellular protection by preventing mutation‐triggered formation of pathological forms of tau. We used crossbreds of TauP301L mice and heterozygous aggrecan mice which are characterized by spontaneous deletion of the aggrecan allele. We analysed the extent of tau pathology in dependence of aggrecan protein amount by applying immunohistochemistry, Western blotting and ELISA. The results clearly indicate that aggrecan has no significant impact on tau aggregation in the brainstem of our mouse model. Still, reduced aggrecan levels were accompanied by increased levels of tau protein and reduced number of Tau‐1‐positive neurons, which indicate an increase in phosphorylation of tau. In conclusion, these data demonstrate a correlation between aggrecan and P301L mutation‐triggered tau expression and phosphorylation in our bigenic mouse model.
Molecules, 2018
The current number of drugs available for the treatment of Alzheimer’s disease (AD) is strongly l... more The current number of drugs available for the treatment of Alzheimer’s disease (AD) is strongly limited and their benefit for therapy is given only in the early state of the disease. An effective therapy should affect those processes which mainly contribute to the neuronal decay. There have been many approaches for a reduction of toxic Aβ peptides which mostly failed to halt cognitive deterioration in patients. The formation of neurofibrillary tangles (NFT) and its precursor tau oligomers have been suggested as main cause of neuronal degeneration because of a direct correlation of their density to the degree of dementia. Reducing of tau aggregation may be a viable approach for the treatment of AD. NFT consist of hyperphosphorylated tau protein and tau hyperphosphorylation reduces microtubule binding. Several protein kinases are discussed to be involved in tau hyperphosphorylation. We developed novel inhibitors of three protein kinases (gsk-3β, cdk5, and cdk1) and discussed their act...
Journal of Alzheimer's Disease, 2018
Long-term exposure to fine particulate matter (PM 2.5) and ozone (O 3) above USEPA standards is a... more Long-term exposure to fine particulate matter (PM 2.5) and ozone (O 3) above USEPA standards is associated with Alzheimer's disease (AD) risk. Metropolitan Mexico City (MMC) children exhibit subcortical pretangles in infancy and cortical tau pre-tangles, NFTs, and amyloid phases 1-2 by the 2nd decade. Given their AD continuum, we measured in 507 normal cerebrospinal fluid (CSF) samples (MMC 354, controls 153, 12.82 ± 6.73 y), a high affinity monoclonal nonphosphorylated tau antibody (non-P-Tau), as a potential biomarker of AD and axonal damage. In 81 samples, we also measured total tau (T-Tau), tau phosphorylated at threonine 181 (P-Tau), amyloid- 1-42 , BDNF, and vitamin D. We documented by electron microscopy myelinated axonal size and the pathology associated with combustion-derived nanoparticles (CDNPs) in anterior cingulate cortex white matter in 6 young residents (16.25 ± 3.34 y). Non-P-Tau showed a strong increase with age significantly faster among MMC versus controls (p = 0.0055). A 1-42 and BDNF concentrations were lower in MMC children (p = 0.002 and 0.03, respectively). Anterior cingulate cortex showed a significant decrease (p = <0.0001) in the average axonal size and CDNPs were associated with organelle pathology. Significant age increases in non-P-Tau support tau changes early in a population with axonal pathology and evolving AD hallmarks in the first two decades of life. Non-P-Tau is an early biomarker of axonal damage and potentially valuable to monitor progressive longitudinal changes along with AD multianalyte classical CSF markers. Neuroprotection of young urbanites with PM 2.5 and CDNPs exposures ought to be a public health priority to halt the development of AD in the first two decades of life.
Molecular Neurobiology, 2017
Amyotrophic lateral sclerosis (ALS) represents a rapidly progressing neurodegenerative disease an... more Amyotrophic lateral sclerosis (ALS) represents a rapidly progressing neurodegenerative disease and is characterized by a degeneration of motor neurons. Motor neurons are particularly susceptible to selective and early degeneration because of their extended axon length and their dependency on the cytoskeleton for its stability, signaling, and axonal transport. The motor neuron cytoskeleton comprises actin filaments, neurofilaments like peripherin, and microtubules. The Transactivating Response Region (TAR) DNA Binding Protein (TDP-43) forms characteristic cytoplasmic aggregates in motor neurons of ALS patients, and at least in part, the pathogenesis of ALS seems to be driven by toxic pTDP-43 aggregates in cytoplasm, which lead to a diminished axon formation and reduced axon length. Diminished axon formation and reduced axon length suggest an interaction of TDP-43 with the cytoskeleton of motor neurons. TDP-43 interacts with several cytoskeletal components, e.g., the microtubuleassociated protein 1B (MAP1B) or the neurofilament light chain (NFL) through direct binding to its RNA. From a clinical perspective, cytoskeletal biomarkers like phosphorylated neurofilament heavy chain (pNFH) and NFL are already clinically used in ALS patients to predict survival, disease progression, and duration. Thus, in this review, we focus on the interaction of TDP-43 with the different cytoskeleton components such as actin filaments, neurofilaments, and microtubules as well as their associated proteins as one aspect in the complex pathogenesis of ALS.
Journal of Alzheimer's Disease, 2016
BACKGROUND: Tau protein, along with its phosphorylated forms (pTau), is one of the established ce... more BACKGROUND: Tau protein, along with its phosphorylated forms (pTau), is one of the established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD), but virtually nothing is known about a potential diagnostic role of non-phosphorylated tau molecules (Non-P-Tau) in CSF. OBJECTIVE: To establish, and analytically and clinically validate the first assay capable to measure concentrations of Non-P-Tau in human CSF. METHODS: An antibody (1G2) was developed that selectively binds to the non-phosphorylated tau molecule at positions 175, 181, and 231, and was used for establishing an ELISA capable to measure Non-P-Tau in human CSF. In the analytical validation, linearity, repeatability of the standard curves, and intra-and interassay precision of the assay were tested, as well as inter-center variability with the QC samples sent either frozen or under ambient temperature. In the clinical part, concentrations of Non-P-Tau were measured in CSF samples from carefully selected AD or mild cognitive impairment (MCI) patients, whose diagnoses were supported by the results of the "classic" CSF biomarkers (n=58), and as well as in CSF samples from non-demented controls (n=42). RESULTS: The 1G2 antibody reacts with decreasing reactivity to tau peptides containing phosphorylation at positions T175, T181 and T231. The average OD of the blank sample was 0.067 ± 0.006; the CV's of the optical densities of the repeated standard curves were between 3.6-15.9%. Median intra-assay range-to-average imprecision of double measurements was 4.8%; inter-assay imprecision of was in the range of 11.2%-15.3%. Non-P-Tau concentrations are stabile in the CSF samples sent to distinct laboratories under ambient temperature; inter-laboratory variation was approximately 30%. The Non-P-Tau CSF concentrations were highly significantly increased in the AD/MCI group (109.2 ± 32.0 pg/mL) compared to the Controls (62.1 ± 9.3 pg/mL, p<0.001). At the cutoff of 78.3 mg/mL, the sensitivity and the specificity were 94.8% and 97.6%, respectively. CONCLUSIONS: For the first time, an assay is reported to reliably measure CSF concentrations of nonphosphorylated tau.
Brain Research Bulletin, 2016
Most neurodegenerative diseases are characterized by intracellular aggregates of insoluble protei... more Most neurodegenerative diseases are characterized by intracellular aggregates of insoluble proteins. As for the majority of these disorders, aetiology and pathogenesis are only poorly understood; current nosological concepts are largely based on these molecular signatures of protein aggregates which also provide valuable tools for neuropathological differential diagnosis. The microtubule associated protein tau is one of these proteins that form intracellular fibrillary deposits in neurons and glial cells of a large variety of disorders today collectively referred to as tauopathies. While dysfunction of tau has unequivocally been shown to be able to cause neurodegeneration, the precise mechanisms of how tau is involved in neurodegenerative disorders is still poorly understood. After research has focused for several decades on the axonal function of tau and on the fibrillar tau aggregation, more recent cell biological studies have opened up new insights into the role of tau at the synapse and in the nucleus. According to currently emerging cell biological concepts, tau might play a role in the regulation of neuronal plasticity in a wide array of neuronal networks. In addition, it might be involved in regulating genome stability. The most intriguing question relevant both to physiological and pathophysiological function of tau is the biological meaning of the large heterogeneity of isoforms of tau which apparently is a rather promiscuous molecule. The present review is divided into two parts. First, we give an overview on the molecular biology and cell biology of tau and its physiological functions. The second part deals with the pathophysiology of tau and description of tauopathies which comprise more than 20 disorders including Alzheimer's disease, progressive supranuclear palsy, cortico basal degeneration, Pick's disease and others.
Alzheimer’s disease belongs to a class of neurodegenerative disorders called “tauopathies” with n... more Alzheimer’s disease belongs to a class of neurodegenerative disorders called “tauopathies” with neurofibrially degeneration associated with the formation of tangles which major component are paired helical filaments (PHF) of hyperphosphorylated tau protein. Tau protein is a microtubule associated protein and its abnormal high degree of phosphorylation in diseased brains is associated with reduced affinity for microtubules, translocation from the neuritic to the somatodendritic compartment. Under normal conditions it is involved in microtubule stabilisation and thereby in the mainteance of axonal transport between soma and presynapse. Loss of microtubule stabelising function as a result of phosphorylation and aggregation is thought to be followed by synaptic regression and cognitive decline long before tangle formation and cell death. Research mainly focused on genetic factors involved in the pathogenesis of tauopathies has lead to the dicovery of several mutation in “familiar” forms...
International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 2009
Neuronal morphology and axonal growth during development are correlated to specific expression of... more Neuronal morphology and axonal growth during development are correlated to specific expression of various microtubule-associated protein tau isoforms. Using RT-PCR and Western blotting we found the unexpected result that the shift from fetal towards adult isoforms does not differ between rat cerebral cortex and cerebellum, two temporally differently developing areas. By immunohistochemistry we observed a cell type specific isoform expression during development and adulthood. The developmental expression of tau isoforms was compared to the appearance of stable microtubules assessed by the immunohistochemical detection of tubulin modifications. The tau isoform shift shows an apparent disconnect to neurogenesis, migration and volume growth, but coincides with the formation of synapses and the appearance of stable microtubules.
Brain, 2019
Using trio exome sequencing, Horn et al. identify de novo gain-of-function mutations in PAK1 in f... more Using trio exome sequencing, Horn et al. identify de novo gain-of-function mutations in PAK1 in four unrelated individuals with intellectual disability, macrocephaly and seizures. PAK1 encodes a p21-activated kinase, which has been implicated in brain development and control of brain size.
PLoS ONE, 2014
Swiprosin-1/EFhd2 (EFhd2) is a cytoskeletal Ca 2+ sensor protein strongly expressed in the brain.... more Swiprosin-1/EFhd2 (EFhd2) is a cytoskeletal Ca 2+ sensor protein strongly expressed in the brain. It has been shown to interact with mutant tau, which can promote neurodegeneration, but nothing is known about the physiological function of EFhd2 in the nervous system. To elucidate this question, we analyzed EFhd2 2/2 /lacZ reporter mice and showed that lacZ was strongly expressed in the cortex, the dentate gyrus, the CA1 and CA2 regions of the hippocampus, the thalamus, and the olfactory bulb. Immunohistochemistry and western blotting confirmed this pattern and revealed expression of EFhd2 during neuronal maturation. In cortical neurons, EFhd2 was detected in neurites marked by MAP2 and co-localized with preand post-synaptic markers. Approximately one third of EFhd2 associated with a biochemically isolated synaptosome preparation. There, EFhd2 was mostly confined to the cytosolic and plasma membrane fractions. Both synaptic endocytosis and exocytosis in primary hippocampal EFhd2 2/2 neurons were unaltered but transport of synaptophysin-GFP containing vesicles was enhanced in EFhd2 2/2 primary hippocampal neurons, and notably, EFhd2 inhibited kinesin mediated microtubule gliding. Therefore, we found that EFhd2 is a neuronal protein that interferes with kinesin-mediated transport.
ChemInform, 2005
Protected mercaptoalkylpyrimidinones: synthesis and test for immunostimulating activity 3-Hydroxy... more Protected mercaptoalkylpyrimidinones: synthesis and test for immunostimulating activity 3-Hydroxyalkyl-pyrimidine 1 reacts with phosphoroxychloride and thioglycolic acid or thiourea to yield pyrimidin-3-ylalkylthioacetic acids 3 or pyrimidin-3-ylalkylthiouroniumsalts 5 respectively. Some of the pyrimidines 3 and 5 showed immunomodulatory activity.
ChemInform, 2004
Background and Objectives Filgotinib (GLPG0634) is a selective inhibitor of Janus kinase 1 (JAK1)... more Background and Objectives Filgotinib (GLPG0634) is a selective inhibitor of Janus kinase 1 (JAK1) currently in development for the treatment of rheumatoid arthritis and Crohn's disease. While less selective JAK inhibitors have shown long-term efficacy in treating inflammatory conditions, this was accompanied by dose-limiting side effects. Here, we describe the pharmacokinetics of filgotinib and its active metabolite in healthy volunteers and the use of pharmacokinetic-pharmacodynamic modeling and simulation to support dose selection for phase IIB in patients with rheumatoid arthritis. Methods Two trials were conducted in healthy male volunteers. In the first trial, filgotinib was administered as single doses from 10 mg up to multiple daily doses of 200 mg. In the second trial, daily doses of 300 and 450 mg for 10 days were evaluated. Non-compartmental analysis was used to determine individual pharmacokinetic parameters for filgotinib and its metabolite. The overall pharmacodynamic activity for the two moieties was assessed in whole blood using interleukin-6-induced phosphorylation of signal-transducer and activator of transcription 1 as a biomarker for JAK1 activity. These data were used to conduct non-linear mixed-effects modeling to investigate a pharmacokinetic/pharmacodynamic relationship. Results Modeling and simulation on the basis of early clinical data suggest that the pharmacokinetics of filgotinib are dose proportional up to 200 mg, in agreement with observed data, and support that both filgotinib and its metabolite contribute to its pharmacodynamic effects. Simulation of biomarker response supports that the maximum pharmacodynamic effect is reached at a daily dose of 200 mg filgotinib. Conclusion Based on these results, a daily dose range up to 200 mg has been selected for phase IIB dose-finding studies in patients with rheumatoid arthritis. Key Points Early clinical studies in healthy volunteers with the first selective Janus kinase 1 inhibitor, filgotinib, showed high exposure to an active metabolite that contributes to its overall pharmacodynamic effects. Dose-dependent pharmacodynamic activity of combined filgotinib and its metabolite was shown in whole blood from healthy volunteers following oral dosing of filgotinib. Pharmacokinetic/pharmacodynamic modeling and simulation show a maximal pharmacodynamic effect is achieved at daily dosing of 200 mg filgotinib, and this dose was selected as the highest in a phase IIB program in patients with rheumatoid arthritis.
Liebigs Annalen der Chemie, 1994
Synthesis of N-Substituted 0x0-and Thioxopyrimidines from 1,2,4-Dithiazolium Salts* 2,4-Diaryl-su... more Synthesis of N-Substituted 0x0-and Thioxopyrimidines from 1,2,4-Dithiazolium Salts* 2,4-Diaryl-substituted 1,3-thiazine-5-carbonitriles 5 , 6, obtained by reaction of 1,2,4-dithiazolium salts 1 with activated cyanoacetates, undergo ring transformations in the presence of primary and secondary amines. Thus, 5 and 6 react with primary amines under mild conditions to give hardly accessible N-3-substituted oxopyrimidine-or thioxopyrimidine-5-carbonitriles 11, 16, with secondary amines to give N-3-unsubstituted pyrimidine derivates 14, 19 and with diamines to give imidazo[ 1,2-c]pyrimidines or pyrimido[ 1,2-c]pyrimidines 23a, b. After alkylation of 1,3-thiazines 6, highly reactive 1,3-thiazinium salts 8 can be isolated.
Molecular Psychiatry
The microtubule-associated protein tau plays a central role in tauopathies such as Alzheimer’s di... more The microtubule-associated protein tau plays a central role in tauopathies such as Alzheimer’s disease (AD). The exact molecular mechanisms underlying tau toxicity are unclear, but aging is irrefutably the biggest risk factor. This raises the question of how cellular senescence affects the function of tau as a microtubule regulator. Here we report that the proportion of tau that is proteolytically cleaved at the caspase-3 site (TauC3) doubles in the hippocampus of senescent mice. TauC3 is also elevated in AD patients. Through quantitative live-cell imaging, we show that TauC3 has a drastically reduced dynamics of its microtubule interaction. Single-molecule tracking of tau confirmed that TauC3 has a longer residence time on axonal microtubules. The reduced dynamics of the TauC3-microtubule interaction correlated with a decreased transport of mitochondria, a reduced processivity of APP-vesicle transport and an induction of region-specific dendritic atrophy in CA1 neurons of the hippo...
Biomolecules, 2022
Tau mutations promote the formation of tau oligomers and filaments, which are neuropathological s... more Tau mutations promote the formation of tau oligomers and filaments, which are neuropathological signs of several tau-associated dementias. Types of neurons in the CNS are spared of tau pathology and are surrounded by a specialized form of extracellular matrix; called perineuronal nets (PNs). Aggrecan, the major PN proteoglycans, is suggested to mediate PNs neuroprotective function by forming an external shield preventing the internalization of misfolded tau. We recently demonstrated a correlation between aggrecan amount and the expression and phosphorylation of tau in a TauP310L-acan mouse model, generated by crossbreeding heterozygous aggrecan mice with a significant reduction of aggrecan and homozygous TauP301L mice. Neurodegenerative processes have been associated with changes of PN structure and protein signature. In this study, we hypothesized that the structure and protein expression of PNs in this TauP310L-acan mouse is regulated by tau. Immunohistochemical and biochemical an...
Einleitung 1 1 EINLEITUNG "Liebe Landsleute, vor kurzem habe ich erfahren, dass ich einer der Mil... more Einleitung 1 1 EINLEITUNG "Liebe Landsleute, vor kurzem habe ich erfahren, dass ich einer der Millionen Amerikaner bin, die an Alzheimer erkrankt sind.[…] Ich beginne nun die Reise, die mich zum Sonnenuntergang meines Lebens führt." [1, 2] Mit diesen Worten verabschiedete sich der an Alzheimer erkrankte Ronald Reagan, am 05.11.1994, von der Amerikanischen Gesellschaft. Der facettenreiche Schauspieler und 40. US-Präsident überlebte den Kampf gegen die progressive, neurodegenerative Krankheit nicht. Wie ihm erging es, laut ALZHEIMER´S DISEASE INTERNATIONAL (ADI), im Jahr 2015 über 47 Millionen Menschen weltweit, die mit einer Demenzerkrankung zu kämpfen hatten-darunter waren 9,9 Millionen Neuerkrankungen. Das bedeutet, dass alle 3,2 Sekunden ein neuer Demenzfall diagnostiziert wird. Das ADI schätzt, dass die Zahl bis 2050 auf 132 Millionen ansteigen wird. [3] In Deutschland leben bis zu 1,2 Millionen Demenzerkrankte. [4] Demenz stellt ein Syndrom mit einem großen Symptompool dar. Mit schleichendem Beginn, geprägt vom Rückgang kognitiver Fähigkeiten, erleben die Betroffenen, anfangs bei vollem Bewusstsein, einen Persönlichtkeitsverlust. Derartige Störungen höherer kortikaler Funktionen sind vorrangig Beeinträchtigungen des Gedächtnisses, der Aufmerksamkeit sowie des Denk-und Urteilsvermögens. [4] Während des progredienten Krankeitsverlaufes sind die Betroffenen nicht mehr in der Lage einfachste Alltagshandlungen ohne Unterstützung zu bewältigen. [5] Gepaart mit Ängsten und Depressionen, entwickeln sich im fortgeschrittenen Stadium vegetative Funktionsstörungen, wie Inkontinenz, das Unvermögen des Kauens, Schluckens und des Atmens. Der so geschwächte Körper bietet viel Angriffsfläche für weitere Komorbiditäten. Nicht selten versterben die Leidtragenden an nicht mehr therapierbaren Infektionen, wie Pneumonien oder Sepsen. Durch soziale Interaktionen können die Betroffenen die ersten Symptome geschickt verschleiern. Treten diese aber in den Vordergrund sind der Zerfall bestimmter Hirnareale und der langsame Rückgang von Nervenzellen schon so weit fortgeschritten, dass das menschliche Gehirn die Fehlfunktion einzelner Abschnitte nicht mehr ausgleichen kann. Ursächlich hierfür sind zum einen neurodegenerative Krankheitsbilder. Hierzu zählen die am häufigsten diagnostizierte Form, die Alzheimer-Demenz (60 bis 70 %), die Lewy-Körperchen-Demenz (15 %) und die Frontotemporale Demenz (5 %). Zum anderen können kleine, kumulierte Infarkte und Läsionen im Gehirn eine Vaskuläre Demenz (10 %) hervorrufen. Fast die Hälfte der Erkrankungen treten als Mischformen auf (Abbildung 1, links, Seite 2). [5] Ihre Differentialdiagnose und Abgrenzung zu anderen neurologischen Erkrankungen ist langwierig und vielschichtig. Für die Diagnosestellung muss die Symptomatik, laut Internationaler statistischer Klassifikation von Krankheiten (ICD-10), mindstestens sechs Monate anhalten. Sie reicht von sozialer, Eigen-, Fremd-, sowie Familienanamnese, über kognitive Tests, wie den Mini Mental Status Test (MMST), den Demenz Detektion Test (DemTect) beziehungsweise den Alzheimer's disease assessment scale cognition-Test (ADAS cog) bis hin zu bildgebenden Verfahren, wie die kraniale Computertomographie (cCT), die kraniale Magnetresonanztomographie (cMRT), Einleitung 2 die Positronen-Emissions-Tomographie (PET) und die Elektroenzephalographie (EEG). Weiterhin können serologische und biochemische Untersuchungen des Blutes sowie die Überprüfung der genetischen Veranlagung hilfreich sein. [4] Eine abschließende Diagnose kann erst post mortem durch eine Gehirnautopsie und histopathologischer Untersuchung erfolgen. Abbildung 1: Ursachen und Prävalenz für Demenzen. Ursachen für Demenzen nach Häufigkeit (links) [6] , Prävalenz für Demenz in Europa nach Altersgruppen, 2013 (rechts) [5]. Demenz ist in der westlichen Welt die vierthäufigste Todesursache nach Herzkreislauf-Erkrankungen, Gewebsneubildungen und zerebrovaskulären Erkrankungen. Dabei ist das Alter der größte Risikofaktor. Die 75-bis 79-Jährigen erkranken viereinhalb Mal häufiger an einer Demenz als ihre zehn Jahre jüngeren Mitmenschen. Die Prävalenzrate steigt von unter einem Prozent, für die 60-bis 65-Jährigen, auf 41 Prozent, für die 90-bis 94-Jährigen (Abbildung 1, rechts). [5] Weiterhin korrelieren Bluthochdruck, Diabetes mellitus, Depressionen im mittleren Alter, soziale Isolation, ein niedriger Bildungsstand sowie ein geringes Einkommen mit dem Risiko an Demenz zu erkranken. [5, 7] Das ADI schätzte die globalen Kosten zur Behandlung und Pflege von Demenzpatienten für das Jahr 2015 auf 818 Milliarden US-Dollar-das entspricht 1,09 Prozent des weltweiten Bruttosozialproduktes-und erwartet einen Anstieg auf bis zu 2000 Milliarden US-Dollar für das Jahr 2030. [3] Alarmierende Zahlen, die die WORLD HEALTH ORGANIZATION (WHO) veranlasst haben mit ihrem GLOBAL ACTION PLAN, von 2017 bis 2025, die Behandlung und die Prävention der Demenz, sowie die soziale Unterstützung und die Menschenrechte der Patienten international zu harmonisieren und außerdem die Forschungskosten um das Zweifache zu erhöhen. [8] Im Folgenden wird speziell auf die Alzheimersche Erkrankung Bezug genommen.
Neuropathology, 2021
Vascular calcification is a common phenomenon in the elderly, predominantly appearing in the basa... more Vascular calcification is a common phenomenon in the elderly, predominantly appearing in the basal ganglia and in the lamina circumvoluta medullaris of the hippocampus. Calcifications are not an inherent feature of Alzheimer's disease. On the other hand, a rare presenile type of dementia with symmetrical Fahr‐type calcifications and numerous neurofibrillary tangles without senile plaques has been described by Kosaka in 1994 and was termed “diffuse neurofibrillary tangles with calcification” (DNTC). We here report a case of Alzheimer's disease with calcifications both in the basal ganglia and in the lamina circumvoluta medullaris of the hippocampus, differing from DNTC by the presence of senile plaques. The calcifications in the hippocampus were not only vascular in nature but also covered amyloid‐β‐ and phosphorylated tau‐positive plaque‐like structures that were linearly arranged along the dentate fascia in the CA1 sector, an unusual finding of pathogenetic interest.
European Journal of Neuroscience, 2020
Selected types of neurons in the central nervous system are associated with a specialized form of... more Selected types of neurons in the central nervous system are associated with a specialized form of extracellular matrix. These so‐called perineuronal nets (PNs) are supramolecular structures surrounding neuronal somata, proximal dendrites and axon initial segments. PNs are involved in the regulation of plasticity and synaptic physiology. In addition, PNs were proposed to carry neuroprotective functions as PN‐ensheathed neurons are mostly spared of tau pathology in brains of Alzheimer patients. Recently, the neuroprotective action of PNs was confirmed experimentally, demonstrating (i) that mainly aggrecan mediates the neuroprotective function of PNs and (ii) that aggrecan seems to generate an external shielding preventing the internalization of pathological forms of tau. In the present study, we aimed at extending these findings and hypothesized that aggrecan further provides an intracellular protection by preventing mutation‐triggered formation of pathological forms of tau. We used crossbreds of TauP301L mice and heterozygous aggrecan mice which are characterized by spontaneous deletion of the aggrecan allele. We analysed the extent of tau pathology in dependence of aggrecan protein amount by applying immunohistochemistry, Western blotting and ELISA. The results clearly indicate that aggrecan has no significant impact on tau aggregation in the brainstem of our mouse model. Still, reduced aggrecan levels were accompanied by increased levels of tau protein and reduced number of Tau‐1‐positive neurons, which indicate an increase in phosphorylation of tau. In conclusion, these data demonstrate a correlation between aggrecan and P301L mutation‐triggered tau expression and phosphorylation in our bigenic mouse model.
Molecules, 2018
The current number of drugs available for the treatment of Alzheimer’s disease (AD) is strongly l... more The current number of drugs available for the treatment of Alzheimer’s disease (AD) is strongly limited and their benefit for therapy is given only in the early state of the disease. An effective therapy should affect those processes which mainly contribute to the neuronal decay. There have been many approaches for a reduction of toxic Aβ peptides which mostly failed to halt cognitive deterioration in patients. The formation of neurofibrillary tangles (NFT) and its precursor tau oligomers have been suggested as main cause of neuronal degeneration because of a direct correlation of their density to the degree of dementia. Reducing of tau aggregation may be a viable approach for the treatment of AD. NFT consist of hyperphosphorylated tau protein and tau hyperphosphorylation reduces microtubule binding. Several protein kinases are discussed to be involved in tau hyperphosphorylation. We developed novel inhibitors of three protein kinases (gsk-3β, cdk5, and cdk1) and discussed their act...
Journal of Alzheimer's Disease, 2018
Long-term exposure to fine particulate matter (PM 2.5) and ozone (O 3) above USEPA standards is a... more Long-term exposure to fine particulate matter (PM 2.5) and ozone (O 3) above USEPA standards is associated with Alzheimer's disease (AD) risk. Metropolitan Mexico City (MMC) children exhibit subcortical pretangles in infancy and cortical tau pre-tangles, NFTs, and amyloid phases 1-2 by the 2nd decade. Given their AD continuum, we measured in 507 normal cerebrospinal fluid (CSF) samples (MMC 354, controls 153, 12.82 ± 6.73 y), a high affinity monoclonal nonphosphorylated tau antibody (non-P-Tau), as a potential biomarker of AD and axonal damage. In 81 samples, we also measured total tau (T-Tau), tau phosphorylated at threonine 181 (P-Tau), amyloid- 1-42 , BDNF, and vitamin D. We documented by electron microscopy myelinated axonal size and the pathology associated with combustion-derived nanoparticles (CDNPs) in anterior cingulate cortex white matter in 6 young residents (16.25 ± 3.34 y). Non-P-Tau showed a strong increase with age significantly faster among MMC versus controls (p = 0.0055). A 1-42 and BDNF concentrations were lower in MMC children (p = 0.002 and 0.03, respectively). Anterior cingulate cortex showed a significant decrease (p = <0.0001) in the average axonal size and CDNPs were associated with organelle pathology. Significant age increases in non-P-Tau support tau changes early in a population with axonal pathology and evolving AD hallmarks in the first two decades of life. Non-P-Tau is an early biomarker of axonal damage and potentially valuable to monitor progressive longitudinal changes along with AD multianalyte classical CSF markers. Neuroprotection of young urbanites with PM 2.5 and CDNPs exposures ought to be a public health priority to halt the development of AD in the first two decades of life.
Molecular Neurobiology, 2017
Amyotrophic lateral sclerosis (ALS) represents a rapidly progressing neurodegenerative disease an... more Amyotrophic lateral sclerosis (ALS) represents a rapidly progressing neurodegenerative disease and is characterized by a degeneration of motor neurons. Motor neurons are particularly susceptible to selective and early degeneration because of their extended axon length and their dependency on the cytoskeleton for its stability, signaling, and axonal transport. The motor neuron cytoskeleton comprises actin filaments, neurofilaments like peripherin, and microtubules. The Transactivating Response Region (TAR) DNA Binding Protein (TDP-43) forms characteristic cytoplasmic aggregates in motor neurons of ALS patients, and at least in part, the pathogenesis of ALS seems to be driven by toxic pTDP-43 aggregates in cytoplasm, which lead to a diminished axon formation and reduced axon length. Diminished axon formation and reduced axon length suggest an interaction of TDP-43 with the cytoskeleton of motor neurons. TDP-43 interacts with several cytoskeletal components, e.g., the microtubuleassociated protein 1B (MAP1B) or the neurofilament light chain (NFL) through direct binding to its RNA. From a clinical perspective, cytoskeletal biomarkers like phosphorylated neurofilament heavy chain (pNFH) and NFL are already clinically used in ALS patients to predict survival, disease progression, and duration. Thus, in this review, we focus on the interaction of TDP-43 with the different cytoskeleton components such as actin filaments, neurofilaments, and microtubules as well as their associated proteins as one aspect in the complex pathogenesis of ALS.
Journal of Alzheimer's Disease, 2016
BACKGROUND: Tau protein, along with its phosphorylated forms (pTau), is one of the established ce... more BACKGROUND: Tau protein, along with its phosphorylated forms (pTau), is one of the established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD), but virtually nothing is known about a potential diagnostic role of non-phosphorylated tau molecules (Non-P-Tau) in CSF. OBJECTIVE: To establish, and analytically and clinically validate the first assay capable to measure concentrations of Non-P-Tau in human CSF. METHODS: An antibody (1G2) was developed that selectively binds to the non-phosphorylated tau molecule at positions 175, 181, and 231, and was used for establishing an ELISA capable to measure Non-P-Tau in human CSF. In the analytical validation, linearity, repeatability of the standard curves, and intra-and interassay precision of the assay were tested, as well as inter-center variability with the QC samples sent either frozen or under ambient temperature. In the clinical part, concentrations of Non-P-Tau were measured in CSF samples from carefully selected AD or mild cognitive impairment (MCI) patients, whose diagnoses were supported by the results of the "classic" CSF biomarkers (n=58), and as well as in CSF samples from non-demented controls (n=42). RESULTS: The 1G2 antibody reacts with decreasing reactivity to tau peptides containing phosphorylation at positions T175, T181 and T231. The average OD of the blank sample was 0.067 ± 0.006; the CV's of the optical densities of the repeated standard curves were between 3.6-15.9%. Median intra-assay range-to-average imprecision of double measurements was 4.8%; inter-assay imprecision of was in the range of 11.2%-15.3%. Non-P-Tau concentrations are stabile in the CSF samples sent to distinct laboratories under ambient temperature; inter-laboratory variation was approximately 30%. The Non-P-Tau CSF concentrations were highly significantly increased in the AD/MCI group (109.2 ± 32.0 pg/mL) compared to the Controls (62.1 ± 9.3 pg/mL, p<0.001). At the cutoff of 78.3 mg/mL, the sensitivity and the specificity were 94.8% and 97.6%, respectively. CONCLUSIONS: For the first time, an assay is reported to reliably measure CSF concentrations of nonphosphorylated tau.
Brain Research Bulletin, 2016
Most neurodegenerative diseases are characterized by intracellular aggregates of insoluble protei... more Most neurodegenerative diseases are characterized by intracellular aggregates of insoluble proteins. As for the majority of these disorders, aetiology and pathogenesis are only poorly understood; current nosological concepts are largely based on these molecular signatures of protein aggregates which also provide valuable tools for neuropathological differential diagnosis. The microtubule associated protein tau is one of these proteins that form intracellular fibrillary deposits in neurons and glial cells of a large variety of disorders today collectively referred to as tauopathies. While dysfunction of tau has unequivocally been shown to be able to cause neurodegeneration, the precise mechanisms of how tau is involved in neurodegenerative disorders is still poorly understood. After research has focused for several decades on the axonal function of tau and on the fibrillar tau aggregation, more recent cell biological studies have opened up new insights into the role of tau at the synapse and in the nucleus. According to currently emerging cell biological concepts, tau might play a role in the regulation of neuronal plasticity in a wide array of neuronal networks. In addition, it might be involved in regulating genome stability. The most intriguing question relevant both to physiological and pathophysiological function of tau is the biological meaning of the large heterogeneity of isoforms of tau which apparently is a rather promiscuous molecule. The present review is divided into two parts. First, we give an overview on the molecular biology and cell biology of tau and its physiological functions. The second part deals with the pathophysiology of tau and description of tauopathies which comprise more than 20 disorders including Alzheimer's disease, progressive supranuclear palsy, cortico basal degeneration, Pick's disease and others.
Alzheimer’s disease belongs to a class of neurodegenerative disorders called “tauopathies” with n... more Alzheimer’s disease belongs to a class of neurodegenerative disorders called “tauopathies” with neurofibrially degeneration associated with the formation of tangles which major component are paired helical filaments (PHF) of hyperphosphorylated tau protein. Tau protein is a microtubule associated protein and its abnormal high degree of phosphorylation in diseased brains is associated with reduced affinity for microtubules, translocation from the neuritic to the somatodendritic compartment. Under normal conditions it is involved in microtubule stabilisation and thereby in the mainteance of axonal transport between soma and presynapse. Loss of microtubule stabelising function as a result of phosphorylation and aggregation is thought to be followed by synaptic regression and cognitive decline long before tangle formation and cell death. Research mainly focused on genetic factors involved in the pathogenesis of tauopathies has lead to the dicovery of several mutation in “familiar” forms...
International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 2009
Neuronal morphology and axonal growth during development are correlated to specific expression of... more Neuronal morphology and axonal growth during development are correlated to specific expression of various microtubule-associated protein tau isoforms. Using RT-PCR and Western blotting we found the unexpected result that the shift from fetal towards adult isoforms does not differ between rat cerebral cortex and cerebellum, two temporally differently developing areas. By immunohistochemistry we observed a cell type specific isoform expression during development and adulthood. The developmental expression of tau isoforms was compared to the appearance of stable microtubules assessed by the immunohistochemical detection of tubulin modifications. The tau isoform shift shows an apparent disconnect to neurogenesis, migration and volume growth, but coincides with the formation of synapses and the appearance of stable microtubules.