Number of Facial Hair Corresponds to Frequency of Spontaneous Face-Touch in Humans.

People all over the world, independent of their culture or background, touch their faces up to 800 times per day. No other part of the body is touched as often as the face. Forehead, nose, and chin-the so-called T-zone of the face-are touched particularly frequently during spontaneous facial self-touches (sFST).

Human iPSC-Derived Neurons with Reliable Synapses and Large Presynaptic Action Potentials.

Understanding the function of the human brain requires determining basic properties of synaptic transmission in human neurons. One of the most fundamental parameters controlling neurotransmitter release is the presynaptic action potential, but its amplitude and duration remain controversial. Presynaptic action potentials have so far been measured with high temporal resolution only in a limited number of vertebrate but not in human neurons.

A novel human tau knock-in mouse model reveals interaction of Abeta and human tau under progressing cerebral amyloidosis in 5xFAD mice.

Background: Hyperphosphorylation and intraneuronal aggregation of the microtubule-associated protein tau is a major pathological hallmark of Alzheimer's disease (AD) brain. Of special interest is the effect of cerebral amyloid beta deposition, the second main hallmark of AD, on human tau pathology. Therefore, studying the influence of cerebral amyloidosis on human tau in a novel human tau knock-in (htau-KI) mouse model could help to reveal new details on their interplay.

Novel effective small-molecule inhibitors of protein kinases related to tau pathology in Alzheimer's disease.

Alzheimer's disease (AD) drugs in therapy are limited to acetylcholine esterase inhibitors and memantine. Newly developed drugs against a single target structure have an insufficient effect on symptomatic AD patients. Novel aromatically anellated pyridofuranes have been evaluated for inhibition of AD-relevant protein kinases cdk1, cdk2, gsk-3b and Fyn.

Tau Protein Modulates Perineuronal Extracellular Matrix Expression in the TauP301L- Mouse Model.

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.

Caspase-cleaved tau is senescence-associated and induces a toxic gain of function by putting a brake on axonal transport.

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.

Senile plaque calcification of the lamina circumvoluta medullaris in Alzheimer's disease.

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).

A glutaminyl cyclase-catalyzed α-synuclein modification identified in human synucleinopathies.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is neuropathologically characterized by degeneration of dopaminergic neurons of the substantia nigra (SN) and formation of Lewy bodies and Lewy neurites composed of aggregated α-synuclein. Proteolysis of α-synuclein by matrix metalloproteinases was shown to facilitate its aggregation and to affect cell viability. One of the proteolysed fragments, Gln79-α-synuclein, possesses a glutamine residue at its N-terminus.

Aggrecan modulates the expression and phosphorylation of tau in a novel bigenic TauP301L - Acan mouse model.

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.

De novo variants in PAK1 lead to intellectual disability with macrocephaly and seizures.

Using trio exome sequencing, we identified de novo heterozygous missense variants in PAK1 in four unrelated individuals with intellectual disability, macrocephaly and seizures. PAK1 encodes the p21-activated kinase, a major driver of neuronal development in humans and other organisms. In normal neurons, PAK1 dimers reside in a trans-inhibited conformation, where each autoinhibitory domain covers the kinase domain of the other monomer.

Hibernation Impairs Odor Discrimination - Implications for Alzheimer's Disease.

Reversible formation of PHF-like phosphorylated tau, an early feature of Alzheimer's disease (AD) was previously shown to occur in torpor during hibernation in the Golden hamster (Syrian hamster, ). Here, we tackled the question to what extent hibernating Golden hamsters can serve as a model for the early stage of AD. During early AD, anosmia, the loss of olfactory function, is a common and typical feature.

Non-Phosphorylated Tau in Cerebrospinal Fluid is a Marker of Alzheimer's Disease Continuum in Young Urbanites Exposed to Air Pollution.

Long-term exposure to fine particulate matter (PM2.5) and ozone (O3) 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.

Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay.

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.

TDP-43 self-interaction is modulated by redox-active compounds Auranofin, Chelerythrine and Riluzole.

Amyotrophic lateral sclerosis (ALS) represents a fatal neurodegenerative disease, which is characterized by a rapid loss of lower and upper motor neurons. As a major neuropathological hallmark, protein aggregates containing the Transactivating Response Region (TAR) DNA Binding Protein (TDP-43) are detectable in about 95% of sporadic ALS patients. TDP-43 interacts with itself physiologically to form liquid droplets, which may progress to pathological aggregates.

TDP-43 and Cytoskeletal Proteins in ALS.

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.

Tau and tauopathies.

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.

Non-Phosphorylated Tau as a Potential Biomarker of Alzheimer's Disease: Analytical and Diagnostic Characterization.

Background: Virtually nothing is known about a potential diagnostic role of non-phospho-epitopes of Tau (Non-P-Tau) in cerebrospinal fluid (CSF).

Objective: To establish and analytically and clinically characterize 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 Tau molecule non-phosphorylated at the positions T175 and T181, and was used in establishing a sandwich ELISA capable to measure Non-P-Tau in human CSF, following analytical and clinical validation of the method.

Tau phosphorylation-associated spine regression does not impair hippocampal-dependent memory in hibernating golden hamsters.

The microtubule-associated protein tau, in its hyperphosphorylated form, is the major component of paired helical filaments and other aggregates in neurodegenerative disorders commonly referred to as "tauopathies". Recent evidence, however, indicates that mislocalization of hyperphosphorylated tau to subsynaptic sites leads to synaptic impairment and cognitive decline even long before formation of tau aggregates and neurodegeneration occur. A similar, but reversible hyperphosphorylation of tau occurs under physiologically controlled conditions during hibernation.

Hook proteins: association with Alzheimer pathology and regulatory role of hook3 in amyloid beta generation.

Defects in intracellular transport are implicated in the pathogenesis of Alzheimer's disease (AD). Hook proteins are a family of cytoplasmic linker proteins that participate in endosomal transport. In this study we show that Hook1 and Hook3 are expressed in neurons while Hook2 is predominantly expressed in astrocytes.

Brain hypometabolism triggers PHF-like phosphorylation of tau, a major hallmark of Alzheimer's disease pathology.

Sporadic Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder of unknown cause characterized by fibrillar accumulation of the Aß-peptide and aggregates of the microtubule-associated protein tau in a hyperphosphorylated form. Already at preclinical stages, AD is characterized by hypometabolic states which are a good predictor of cognitive decline. Here, we summarize recent evidence derived from the study of hibernating animals that brain hypometabolism can trigger PHF-like hyperphosphorylation of tau.

Tenascin-R promotes assembly of the extracellular matrix of perineuronal nets via clustering of aggrecan.

Perineuronal nets (PNs) in the brains of tenascin-R-deficient (tn-r(-/-)) mice develop in temporal concordance with those of wild-type (tn-r(+/+)) mice. However, the histological appearance of PNs is abnormal in adult tn-r(-/-) mice. Here, we investigated whether similar defects are also seen in dissociated and organotypic cultures from hippocampus and forebrain of tn-r(-/-) mice and whether the structure of PNs could be normalized.

The Ca2+ sensor protein swiprosin-1/EFhd2 is present in neurites and involved in kinesin-mediated transport in neurons.

Swiprosin-1/EFhd2 (EFhd2) is a cytoskeletal Ca2+ 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-/-/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.

Pin1 promotes degradation of Smad proteins and their interaction with phosphorylated tau in Alzheimer's disease.

Aims: Neurodegeneration in Alzheimer's disease (AD) is characterized by pathological protein aggregates and inadequate activation of cell cycle regulating proteins. Recently, Smad proteins were identified to control the expression of AD relevant proteins such as APP, CDK4 and CDK inhibitors, both critical regulators of cell cycle activation. This might indicate a central role for Smads in AD pathology where they show a substantial deficiency and disturbed subcellular distribution in neurones.

Axotrophin/MARCH7 acts as an E3 ubiquitin ligase and ubiquitinates tau protein in vitro impairing microtubule binding.

Tau is the major microtubule-associated protein in neurons involved in microtubule stabilization in the axonal compartment. Changes in tau gene expression, alternative splicing and posttranslational modification regulate tau function and in tauopathies can result in tau mislocalization and dysfunction, causing tau aggregation and cell death. To uncover proteins involved in the development of tauopathies, a yeast two-hybrid system was used to screen for tau-interacting proteins.

Tau oligomers impair artificial membrane integrity and cellular viability.

The microtubule-associated protein Tau is mainly expressed in neurons, where it binds and stabilizes microtubules. In Alzheimer disease and other tauopathies, Tau protein has a reduced affinity toward microtubules. As a consequence, Tau protein detaches from microtubules and eventually aggregates into β-sheet-containing filaments.