Eckhard Mandelkow

Deutsches Zentrum für Neurodegenerative Erkrankungen | DZNE · RG Structural Principles of Neurodegeneration (Bonn)

Tau is an intrinsically disordered neuronal protein in the central nervous system. Aggregated Tau is the main component of neurofibrillary tangles observed in Alzheimer’s disease. In vitro, Tau aggregation can be triggered by polyanionic co-factors, like RNA or heparin. At different concentration ratios, the same polyanions can induce Tau condensat...

Reorientational dynamics of intrinsically disordered proteins (IDPs) contain multiple motions often clustered around three motional modes: ultrafast librational motions of amide groups, fast local backbone conformational fluctuations and slow chain segmental motions. This dynamic picture is mainly based on 15N NMR relaxation studies of IDPs at rela...

Tau is a microtubule-associated protein found mainly in the axons of neurons in the brain. Abnormal changes in Tau (e.g., aggregation, hyperphosphorylation) are hallmarks of Alzheimer’s disease. Two processes of relocalization of Tau may be related to early states of the pathology and have received much attention: (1) the redistribution of Tau with...

Tau is an intrinsically disordered protein that binds and stabilizes axonal microtubules (MTs) in neurons of the central nervous system. The binding of Tau to MTs is mediated by its repeat domain and flanking proline-rich domains. The positively charged (basic) C-terminal half of Tau also mediates the assembly Tau into fibrillar aggregates in Alzhe...

Cerebral glucose hypometabolism is a typical hallmark of Alzheimer’s disease (AD), usually associated with ongoing neurodegeneration and neuronal dysfunction. However, underlying pathological processes are not fully understood and reproducibility in animal models is not well established. The aim of the present study was to investigate the regional...

Biomolecular condensation of the neuronal microtubule-associated protein Tau (MAPT) can be induced by coacervation with polyanions like RNA, or by molecular crowding. Tau condensates have been linked to both functional microtubule binding and pathological aggregation in neurodegenerative diseases. We find that molecular crowding and coacervation wi...

Background: Accumulation of tau is a characteristic hallmark of several neurodegenerative diseases and is associated with neuronal hypoactivity and presynaptic dysfunction. Oral administration of the adenosine A1 receptor antagonist rolofylline (KW-3902) has been shown previously to reverse spatial memory deficits and to normalize the basic synapti...

Microtubule-associated protein tau is a naturally unfolded protein that can modulate a vast array of physiological processes through direct or indirect binding with molecular partners. Aberrant tau homeostasis has been implicated in the pathogenesis of several neurodegenerative disorders, including Alzheimer’s disease (AD). In this study, we perfor...

Biomolecular condensation of the neuronal microtubule-associated protein Tau (MAPT) can be induced by coacervation with polyanions like RNA, or by molecular crowding. Tau condensates have been linked to both functional microtubule binding and pathological aggregation in neurodegenerative diseases. We find that molecular crowding and coacervation wi...

Background Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder that mainly affects older adults. One of the pathological hallmarks of AD is abnormally aggregated Tau protein that forms fibrillar deposits in the brain. In AD, Tau pathology correlates strongly with clinical symptoms, cognitive dysfu...

Two hexapeptide motifs within Tau, designated PHF6* (275VQIINK280) and PHF6 (306VQIVYK311), are known to drive Tau aggregation, making them attractive targets for the development of Tau aggregation inhibitors for therapeutic options. Employing mirror‐image phage display with a large peptide library, we have identified PHF6* fibril binding peptides...

Tau misfolding and assembly is linked to a number of neurodegenerative diseases collectively described as tauopathies, including Alzheimer’s disease (AD) and Parkinson’s disease. Anionic cellular membranes, such as the cytosolic leaflet of the plasma membrane, are sites that concentrate and neutralize tau, primarily due to electrostatic interaction...

The functions of the neuronal microtubule-associated protein Tau in the central nervous system are regulated by manifold posttranslational modifications at more than 50 sites. Tau in healthy neurons carries multiple phosphate groups, mostly in its microtubule assembly domain. Elevated phosphorylation and aggregation of Tau are widely considered pat...

Alzheimer’s disease and other tauopathies are associated with neurofibrillary tangles composed of Tau protein, as well as toxic Tau oligomers. Therefore, inhibitors of pathological Tau aggregation are potentially useful candidates for future therapies targeting Tauopathies. Two hexapeptides within Tau, designated PHF6* (275‐VQIINK‐280) and PHF6 (30...

Background: One of the major hallmarks of Alzheimer's disease (AD)is the aberrant modification and aggregation of the microtubule-associated protein Tau . The extent of Tau pathology correlates with cognitive decline, strongly implicating Tau in the pathogenesis of the disease. Because the inhibition of Tau aggregation may be a promising therapeut...

The aggregation of hyperphosphorylated tau into amyloid fibrils is closely linked to the progression of Alzheimer’s disease. To gain insight into the link between amyloid structure and disease, the three-dimensional structure of tau fibrils has been studied using solid-state NMR (ssNMR) and cryogenic electron microscopy (cryo-EM). The proline-rich...

Tau aggregation into amyloid fibers based on the cross-beta structure is a hallmark of several Tauopathies, including Alzheimer Disease (AD). Trans-cellular propagation of Tau with pathological conformation has been suggested as a key disease mechanism. This is thought to cause the spreading of Tau pathology in AD by templated conversion of naive T...

Cellular condensation of intrinsically disordered proteins (IDPs) through liquid–liquid phase separation (LLPS) allows dynamic compartmentalization and regulation of biological processes. The IDP tau, which promotes the assembly of microtubules and is hyperphosphorylated in Alzheimer's disease, undergoes LLPS in solution and on the surface of micro...

Aktives Tau rekrutiert Tubulin in flüssigkeitsähnliche Kondensate und fördert die Polymerisation in Mikrotubuli. Bei der Phosphorylierung am krankheitsassoziierten AT180‐Epitop werden intramolekulare Salzbrücken gebildet und die Aktivität der Tubulinpolymerisation geht verloren. Abstract Die zelluläre Kondensation von intrinsisch ungeordneten Prot...

Abnormal changes of neuronal tau-protein, such as phosphorylation and aggregation, are considered hallmarks of cognitive deficits in Alzheimer disease. Abnormal phosphorylation is thought to precede aggregation and therefore to promote aggregation, but the nature and extent of phosphorylation remained ill-defined. Tau contains ~85 potential phospho...

Abnormal changes in the neuronal microtubule-associated protein Tau, such as hyperphosphorylation and aggregation, are considered hallmarks of cognitive deficits in Alzheimer disease. Hyperphosphorylation is thought to take place before aggregation, and therefore it is often assumed that phosphorylation predisposes Tau towards aggregation. However,...

The aggregation of the intrinsically disordered tau protein into highly ordered β-sheet-rich fibrils is implicated in the pathogenesis of a range of neurodegenerative disorders. The mechanism of tau fibrillogenesis remains unresolved, particularly early events that trigger the misfolding and assembly of the otherwise soluble and stable tau. We inve...

Intrinsically disordered proteins (IDPs) can be degraded in a ubiquitin-independent process by the 20 S proteasome. Decline in 20 S activity characterizes neurodegenerative diseases. Here, we examine 20 S degradation of IDP tau, a protein that aggregates into insoluble deposits in Alzheimer’s disease. We show that cleavage of tau by the 20 S protea...

Tau aggregation into amyloid fibers based on the cross-beta structure is a hallmark of several Tauopathies, including Alzheimer Disease (AD). Trans-cellular propagation of Tau with pathological conformation has been suggested as a key disease mechanism. This is thought to cause the spreading of Tau pathology in AD by templated conversion of naive T...

Tau aggregation into amyloid fibers based on the cross-beta structure is a hallmark of several Tauopathies, including Alzheimer Disease (AD). Trans-cellular propagation of Tau with pathological conformation has been suggested as a key disease mechanism. This is thought to cause the spreading of Tau pathology in AD by templated conversion of naive T...

Tau aggregation into amyloid fibers based on the cross-beta structure is a hallmark of several Tauopathies, including Alzheimer Disease (AD). Trans-cellular propagation of Tau with pathological conformation has been suggested as a key disease mechanism. This is thought to cause the spreading of Tau pathology in AD by templated conversion of naive T...

The aggregation of the intrinsically disordered tau protein into highly ordered beta-sheet fibrils is implicated in many neurodegenerative disorders. Fibrillation mechanism remains unresolved, particularly early events that trigger tau misfolding and assembly. We investigated the role membrane plays in modulating aggregation of three tau variants,...

Alzheimer’s disease (AD) pathology precedes the onset of clinical symptoms by several decades. Thus, biomarkers are required to identify prodromal disease stages to allow for the early and effective treatment. The methoxy-X04-derivative BSC4090 is a fluorescent ligand which was designed to target neurofibrillary tangles in AD. BSC4090 staining was...

p>Almost 50 million people worldwide are affected by Alzheimer’s disease (AD), the most common neurodegenerative disorder. Development of disease-modifying therapies would benefit from reliable, non-invasive positron emission tomography (PET) biomarkers for early diagnosis, monitoring of disease progression, and assessment of therapeutic effects. T...

Cells form and use biomolecular condensates to execute biochemical reactions. The molecular properties of non-membrane-bound condensates are directly connected to the amino acid content of disordered protein regions. Lysine plays an important role in cellular function, but little is known about its role in biomolecular condensation. Here we show th...

Missorting of MAPT/Tau represents one of the early signs of neurodegeneration in Alzheimer disease. The triggers for this are still a matter of debate. Here we investigated the sorting mechanisms of endogenous MAPT in mature primary neurons using microfluidic chambers (MFCs) where cell compartments can be observed separately. Blocking protein degra...

Liquid-liquid phase separation of proteins enables the formation of non-membrane-bound organelles in cells and is associated with human disease. Little is known however about the structure and dynamics of proteins in conditions of liquid phase separation. Using NMR spectroscopy we here show that the conversion of the repeat region of the Alzheimer’...

Tau aggregation is a hallmark of a group of neurodegenerative diseases termed Tauopathies. Reduction of aggregation-prone Tau has emerged as a promising therapeutic approach. Here, we show that an anti-aggregant Tau fragment (F3ΔKPP, residues 258–360) harboring the ΔK280 mutation and two proline substitutions (I²⁷⁷P & I³⁰⁸P) in the repeat domain ca...

Background Aggregation of tau proteins is a distinct hallmark of tauopathies and has been a focus of research and clinical trials for Alzheimer’s Disease. Recent reports have pointed towards a toxic effect of soluble or oligomeric tau in the spreading of tau pathology in Alzheimer’s disease. Here we investigated the effects of expressing human tau...

Tau is a microtubule-associated protein (MAP) that is mainly sorted into the axons in physiological conditions, but missorted in Alzheimer Disease and related tauopathies. The mechanism(s) of axonal targeting of Tau protein are still a matter of debate. Several possibilities for the axonal localization of Tau protein have been proposed: (1) Targeti...

We have developed a cell-based phenotypic automated high-content screening approach for N2a cells expressing the pro-aggregant repeat domain of tau protein (tauRDΔK), which allows analysis of a chemogenomic library of 1649 compounds for their effect on the inhibition or stimulation of intracellular tau aggregation. We identified several inhibitors...

The molecular chaperone Hsp90 is critical for the maintenance of cellular homeostasis and represents a promising drug target. Despite increasing knowledge on the structure of Hsp90, the molecular basis of substrate recognition and pro-folding by Hsp90/co-chaperone complexes remains unknown. Here, we report the solution structures of human full-leng...

Tau is the major constituent of neurofibrillary tangles in Alzheimer's disease (AD), but the mechanism underlying tau-associated neural damage remains unclear. Here, we show that tau can directly interact with nucleoporins of the nuclear pore complex (NPC) and affect their structural and functional integrity. Pathological tau impairs nuclear import...

Missorting of MAPT/Tau represents one of the early signs of neurodegeneration in Alzheimer disease. The triggers for this are still a matter of debate. Here we investigated the sorting mechanisms of endogenous MAPT in mature primary neurons using microfluidic chambers (MFCs) where cell compartments can be observed separately. Blocking protein degra...

Deposition of Tau aggregates in patient’s brains is a hallmark of several neurodegenerative diseases collectively called Tauopathies. One of the most studied Tauopathies is Alzheimer disease (AD) in which Tau protein aggregates into filaments and coalesces into neurofibrillary tangles. The distribution of Tau filaments is a reliable indicator of th...

Mutations in the gene encoding Tau (MAPT-microtubule-associated protein tau) cause a group of neurodegenerative diseases called tauopathies. A recently identified Tau variant, p.A152T, has been reported as a risk factor for frontotemporal dementia-related disorders and Alzheimer disease. However, the mechanism for the pathologies still remain poorl...

A 2-dimensional high-throughput screening method is presented to select peptide sequences from large peptide libraries for precision formulation additives, having a high capacity to specifically host a drug of interest and provide tailored drug release properties. The identified sequences are conjugated with poly(ethylene glycol) (PEG) to obtain pe...

Misfolding and aggregation of the neuronal, microtubule associated protein tau is involved in the pathogenesis of Alzheimer’s disease and tauopathies. It has been proposed that neuronal membranes could play a role in tau release, internalization and aggregation, and that tau aggregates could exert toxicity via membrane permeabilization. Whether and...

Expanded View Figures PDF

The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid-liquid phase separation (LLPS) under cellular conditions and that phase-separated tau droplets can serve as an intermediate toward tau aggre...

Fig. S1 Proteolytic susceptibility of different mutant tau proteins. Fig. S2 Association of the CMA fluorescent reporter with lysosomes. Fig. S3 Resistance to stress of cells expressing disease‐related mutant tau proteins. Fig. S4 Effect of disease‐associated mutant tau proteins on macroautophagy flux. Fig. S5 Effect of disease‐related mutant t...

The microtubule-associated protein Tau promotes the polymerization of tubulin and modulates the function of microtubules. Because of the dynamic nature of the Tau/tubulin interaction, the structural basis of this complex has remained largely elusive. Using a combination of NMR methods optimized for ligand-receptor interactions and site-directed mut...

The microtubule-associated protein Tau promotes the polymerization of tubulin and modulates the function of microtubules. As a consequence of the dynamic nature of the Tau-tubulin interaction, the structural basis of this complex has remained largely elusive. By using NMR methods optimized for ligand-receptor interactions in combination with site-d...

Emerging experimental evidence suggests that the spread of tau pathology in the brain in Tauopathies reflects the propagation of abnormal tau species along neuroanatomically connected brain areas. This propagation could occur through a “prion-like” mechanism involving transfer of abnormal tau seeds from a “donor cell” to a “recipient cell” and recr...

Microtubule-associated proteins regulate microtubule dynamics, bundle actin filaments, and cross-link actin filaments with microtubules. In addition, aberrant interaction of the microtubule-associated protein Tau with filamentous actin is connected to synaptic impairment in Alzheimer’s disease. Here we provide insight into the nature of interaction...