dGAE(297-391) Tau Fragment Promotes Formation of Chronic Traumatic Encephalopathy-Like Tau Filaments.

The microtubule-associated protein tau forms disease-specific filamentous aggregates in several different neurodegenerative diseases. In order to understand how tau undergoes misfolding into a specific filament type and to control this process for drug development purposes, it is crucial to study in vitro tau aggregation methods and investigate the structures of the obtained filaments at the atomic level. Here, we used the tau fragment dGAE, which aggregates spontaneously, to seed the formation of full-length tau filaments.

Monoclonal antibodies targeting two immunodominant epitopes on the Spike protein neutralize emerging SARS-CoV-2 variants of concern.

Background: The emergence of new SARS-CoV-2 variants of concern B.1.1.

Impact of mesenchymal stem cells derived conditioned media on neural progenitor cells.

Neurodegenerative diseases are common problem for companion animals. Due to the limited ability of injured axons to regenerate, innovative therapies combined with rehabilitation have been applied and evaluated. Among them, stem cells and their conditioned media implantation, which can ameliorate damaged tissue has been suggested as a promising treatment strategy.

The engagement of microglia in tau-targeted immunotherapy in Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive memory decline, histopathological lesions such as amyloid β plaques and neurofibrillary tangles, and neuroinflammation driven by glial cells. Microglia, the innate immune cells of the brain, dynamically survey their environment for signs of infection and cell damage. Although our understanding of microglia and their modes of activation has expanded in recent years, their role in AD is still not completely understood.

Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation.

Immunotherapies targeting pathological tau have recently emerged as a promising approach for treatment of neurodegenerative disorders. We have previously showed that the mouse antibody DC8E8 discriminates between healthy and pathological tau, reduces tau pathology in murine tauopathy models and inhibits neuronal internalization of AD tau species in vitro.Here we show, that DC8E8 and antibodies elicited against the first-in-man tau vaccine, AADvac1, which is based on the DC8E8 epitope peptide, both promote uptake of pathological tau by mouse primary microglia.

Location of neonatal microglia drives small extracellular vesicles content and biological functions .

Combining proteomics and systems biology approaches, we demonstrate that neonatal microglial cells derived from two different CNS locations, cortex and spinal cord, and cultured displayed different phenotypes upon different physiological or pathological conditions. These cells also exhibited greater variability in terms of cellular and small extracellular vesicles (sEVs) protein content and levels. Bioinformatic data analysis showed that cortical microglia exerted anti-inflammatory and neurogenesis/tumorigenesis properties, while the spinal cord microglia were more inflammatory.

Therapeutic antibody targeting microtubule-binding domain prevents neuronal internalization of extracellular tau via masking neuron surface proteoglycans.

Pathologically altered tau protein is a common denominator of neurodegenerative disorders including Alzheimer's disease (AD) and other tauopathies. Therefore, promising immunotherapeutic approaches target and eliminate extracellular pathogenic tau species, which are thought to be responsible for seeding and propagation of tau pathology. Tau isoforms in misfolded states can propagate disease pathology in a template-dependent manner, proposed to be mediated by the release and internalization of extracellular tau.

Microglia display modest phagocytic capacity for extracellular tau oligomers.

Background: Abnormal misfolded tau protein is a driving force of neurofibrillary degeneration in Alzheimer's disease. It has been shown that tau oligomers play a crucial role in the formation of intracellular neurofibrillary tangles. They are intermediates between soluble tau monomers and insoluble tau filaments and are suspected contributors to disease pathogenesis.

N-terminal truncation of microtubule associated protein tau dysregulates its cellular localization.

Tau protein is a member of microtubule-associated protein family. Under pathological conditions, tau undergoes multiple modifications that lead to the formation of insoluble deposits in neurons, resulting in neuronal dysfunction in several neurodegenerative disorders collectively called tauopathies, with Alzheimer's disease being the most frequent example. This typical cytosolic protein has been shown to translocate into the nucleus and participate in DNA protection upon stress conditions.

Can we teach old dogs new tricks? Neuroprotective cell therapy in Alzheimer's and Parkinson's disease.

Human neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease represent unmet medical need. There is no effective cure available on the market. Several novel therapeutic approaches targeting fundamental features of these disorders have been proposed during the last two decades.

Misfolded truncated protein τ induces innate immune response via MAPK pathway.

Neuroinflammation plays a key role in the pathogenesis of Alzheimer's disease and related tauopathies. We have previously shown that expression of nonmutated human truncated τ (151-391, 4R), derived from sporadic Alzheimer's disease, induced neurofibrillary degeneration accompanied by microglial and astroglial activation in the brain of transgenic rats. The aim of the current study was to determine the molecular mechanism underlying innate immune response induced by misfolded truncated τ.

Hyperphosphorylated truncated protein tau induces caspase-3 independent apoptosis-like pathway in the Alzheimer's disease cellular model.

Neurofibrillary degeneration and neuronal loss represent key pathological hallmarks of Alzheimer's disease (AD). It has been demonstrated that the decrease of total neuronal numbers correlates with the presence of neurofibrillary degeneration in AD brain. In order to unravel the mechanism leading to the cell death in AD, we developed a stably transfected human neuroblastoma cellular model with doxycycline-regulatable expression of AD truncated tau protein (AT tau, 151-391 4R).

Human truncated tau is using a different mechanism from amyloid-beta to damage the blood-brain barrier.

Recent findings showed that vascular dysfunction is an integral part of Alzheimer's disease pathology. Increased microvascular permeability is mainly associated with cerebrovascular amyloid-beta deposits. In contrast, little is known about the relationship between functional impairment of the blood-brain barrier and misfolded tau.

Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo.

Truncated tau protein is the characteristic feature of human sporadic Alzheimer's disease. We have identified truncated tau proteins conformationally different from normal healthy tau. Subpopulations of these structurally different tau species promoted abnormal microtubule assembly in vitro suggesting toxic gain of function.