Propagation Of Tau Research Articles

The Prion-Like Behavior of Assembled Tau in Transgenic Mice.

Tauopathies constitute neurodegenerative diseases that are characterized by the intracellular deposition of filaments made of hyperphosphorylated tau protein. The pattern of tau deposition in Alzheimer's disease follows a stereotypical progression, with the first lesions appearing in the locus coeruleus and entorhinal cortex, from where they appear to spread to the hippocampus and neocortex. Propagation of pathological tau is also characteristic of argyrophilic grain disease, where the lesions seem to spread through distinct regions of the limbic system. In chronic traumatic encephalopathy, tauopathy appears to spread from the neocortex to the brainstem. These findings implicate neuron-to-neuron propagation of tau aggregates. Isoform compositions and morphologies of tau filaments can differ between tauopathies, which is consistent with the existence of distinct tau strains. Here, we review recent findings that support prion-like mechanisms in the pathogenesis of tauopathies through the experimental use of transgenic mice.

Genetic risk factors of Alzheimer's disease and cell-to-cell transmission of Tau

In Alzheimer’s disease (AD), loss of neurons and synapses parallels the formation of neurofibrillary tangles, protein aggregates mainly composed of hyperphosphorylated and aggregated Tau protein. Tau is mostly a cytosolic protein but can also be secreted by neurons. Cell-to-cell transfer of misfolded Tau protein plays a key role in the spread of neurofibrillary pathology between brain regions in AD and other tauopathies. Advances in genome-wide technologies have identified a large number of genetic risk factors for late-onset AD (LOAD). Currently, it remains unknown if genetic factors influence disease risk or progression rate by altering cell-to-cell propagation of Tau. Several LOAD risk genes are functionally associated with endocytic trafficking providing a potential link to Tau secretion and uptake. Recently, a LOAD risk gene FRMD4A was shown to regulate Tau secretion via a pathway linked to presynaptic vesicle machinery and polarity signaling. Tau release is linked to neuronal activity, and genetic factors that affect presynaptic vesicle release in the aging brain may also influence disease progression in AD and other tauopathies. In this mini review, we summarize the recent literature with a focus on the role of FRMD4A-cytohesin-Arf6 pathway and presynaptic vesicle machinery in the secretion of Tau.

Propagation of tau pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies.

Tau is a microtubule-associated protein and a key regulator of microtubule stabilization as well as the main component of neurofibrillary tangles-a principle neuropathological hallmark of Alzheimer's disease (AD)-as well as pleomorphic neuronal and glial inclusions in neurodegenerative tauopathies. Cross-sectional studies of neurofibrillary pathology in AD reveal a stereotypic spatiotemporal pattern of neuronal vulnerability that correlates with disease severity; however, the relationship of this pattern to disease progression is less certain and exceptions to the typical pattern have been described in a subset of AD patients. The basis for the selective vulnerability of specific populations of neurons to tau pathology and cell death is largely unknown, although there have been a number of hypotheses based upon shared properties of vulnerable neurons (e.g., degree of axonal myelination or synaptic plasticity). A recent hypothesis for selective vulnerability takes into account the emerging science of functional connectivity based upon resting state functional magnetic resonance imaging, where subsets of neurons that fire synchronously define patterns of degeneration similar to specific neurodegenerative disorders, including various tauopathies. In the past 6 years, the concept of tau propagation has emerged from numerous studies in cell and animal models suggesting that tau moves from cell-to-cell and that this may trigger aggregation and region-to-region spread of tau pathology within the brain. How the spread of tau pathology relates to functional connectivity is an area of active investigation. Observations of templated folding and propagation of tau have prompted comparisons of tau to prions, the pathogenic proteins in transmissible spongiform encephalopathies. In this review, we discuss the most compelling studies in the field, discuss their shortcomings and consider their implications with respect to human tauopathies as well as the controversy that tauopathies may be prion-like disorders.

Microglia: Tau distributors.

Microglia contribute to the propagation of tau between brain regions in mice, by phagocytosis and release of the protein.

Depletion of microglia and inhibition of exosome synthesis halt tau propagation

Accumulation of pathological tau protein is a major hallmark of Alzheimer's disease. Tau protein spreads from the entorhinal cortex to the hippocampal region early in the disease. Microglia, the primary phagocytes in the brain, are positively correlated with tau pathology, but their involvement in tau propagation is unknown. We developed an adeno-associated virus-based model exhibiting rapid tau propagation from the entorhinal cortex to the dentate gyrus in 4 weeks. We found that depleting microglia dramatically suppressed the propagation of tau and reduced excitability in the dentate gyrus in this mouse model. Moreover, we demonstrate that microglia spread tau via exosome secretion, and inhibiting exosome synthesis significantly reduced tau propagation in vitro and in vivo. These data suggest that microglia and exosomes contribute to the progression of tauopathy and that the exosome secretion pathway may be a therapeutic target.

Extensive deamidation at asparagine residue 279 accounts for weak immunoreactivity of tau with RD4 antibody in Alzheimer’s disease brain

BackgroundIntracytoplasmic inclusions composed of filamentous tau proteins are defining characteristics of neurodegenerative tauopathies, but it remains unclear why different tau isoforms accumulate in different diseases and how they induce abnormal filamentous structures and pathologies. Two tau isoform-specific antibodies, RD3 and RD4, are widely used for immunohistochemical and biochemical studies of tau species in diseased brains.ResultsHere, we show that extensive irreversible post-translational deamidation takes place at asparagine residue 279 (N279) in the RD4 epitope of tau in Alzheimer’s disease (AD), but not corticobasal degeneration (CBD) or progressive supranuclear palsy (PSP), and this modification abrogates the immunoreactivity to RD4. An antiserum raised against deamidated RD4 peptide specifically recognized 4R tau isoforms, regardless of deamidation, and strongly stained tau in AD brain. We also found that mutant tau with N279D substitution showed reduced ability to bind to microtubules and to promote microtubule assembly.ConclusionThe biochemical and structural differences of tau in AD from that in 4R tauopathies found in this study may therefore have implications for prion-like propagation of tau.

Mechanism of tau transfer: insights from cell culture and animal models

Objective Tau inclusions composed of tau fibrils are one of the key hallmarks of Alzheimer’s disease and other tauopathies. Studies from transgenic animal models and human AD pathological cases suggest that tau inclusions spread from the transentorhinal cortex to mono and transynaptically connected regions of the hippocampus and neocortical regions. This study examines cell-to-cell propagation of pathological tau in cell culture and in vivo animal models.