Accumulation Of Tau In Neurons Research Articles

DNA Damage as an Early Marker of Senescence in Tauopathies

AbstractBackgroundHyperphosphorylated tau accumulation in neurons and astrocytes is a pathological hallmark of a class of neurodegenerative disorders known as “tauopathies”, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). Previous research investigating the toxic effects of astrocytic tau pathology identified the DNA damage marker p16 in astrocytes from post‐mortem human cases of AD and FTD. DNA damage is one of many markers of cellular senescence, a state in which cells undergo irreversible cell cycle arrest. Senescence initiation can also be identified via the expression of phosphorylated histone H2AX (gamma‐H2AX) and cyclin‐dependent kinase inhibitor p21. Senescence in astrocytes leads to reduced functional support for neurons. While recognized, the role of senescent astrocytes in tauopathies is not well understood. Here, we sought to determine how expression of other DNA damage markers, such as gamma‐H2AX and p21, and the DAMP protein HMGB1 varies across different tauopathies.MethodImmunohistochemistry (IHC) was performed on postmortem human frontal cortex tissue of CTE (n = 3), AD (N = 3), PSP (n = 3), CBD (n = 3), Healthy (n = 1) and glioblastoma (GBM) (n = 1) cases with antibodies against markers of early senescence gamma H2A.x (yH2A.x) and p21, late senescence, p16, and a senescence‐associated secretory phenotype, HMGB1. Positively stained nuclei were quantified. Immunofluorescence (IF) was employed on postmortem cases using either glial fibrillary acidic protein (GFAP) or Neurofilament H (NF‐H) antibodies with yH2A.x, p16, p21 and HMGB1 markers in order to qualitatively and quantitatively measure the prevalence of senescent astrocytes and neurons in tauopathies.ResultImmunohistochemistry revealed yH2Ax expression was observed in AD, PSP, and CBD cases. Immunofluorescence experiments employing yH2AX co‐stained with astrocytic and neuronal markers revealed expression in AD, PSP and CBD cases. Minimal expression of yH2Ax was revealed in the CTE and healthy control cases. Results from p21 stains were inconclusive. Preliminary evidence reveals HMGB1 expression in CBD and PSP cases utilizing IF techniques, and p16 expression in cells employing IHC.ConclusionOverall, results indicate that DNA damage may be broadly associated with astrocytes in tauopathies. Utilizing alternative approaches to recognize and evaluate astrocyte senescence in post‐mortem human tissue will provide further insight into these findings.

Diagnostic and therapeutic targeting of pathological tau proteins in neurodegenerative disorders.

Tauopathies, characterized by fibrillar tau accumulation in neurons and glial cells, constitute a major neuropathological category of neurodegenerative diseases. Neurofibrillary tau lesions are strongly associated with cognitive deficits in these diseases, but the causal mechanisms underlying tau-induced neuronal dysfunction remain unresolved. Recent advances in cryo-electron microscopy examination have revealed various core structures of tau filaments from different tauopathy patients, which can be used to classify tauopathies. In vivo visualization of tau pathology is now available using several tau positron emission tomography tracers. Among these radioprobes, PM-PBB3 allows high-contrast imaging of tau deposits in the brains of patients with diverse disorders and tauopathy mouse models. Selective degradation of pathological tau species by the ubiquitin-proteasome system or autophagy machinery is a potential therapeutic strategy. Alternatively, the non-cell-autonomous clearance of pathological tau species through neuron-glia networks could be reinforced as a disease-modifying treatment. In addition, the development of neuroinflammatory biomarkers is required for understanding the contribution of immunocompetent cells in the brain to preventing neurodegeneration. This review provides an overview of the current research and development of diagnostic and therapeutic agents targeting divergent tau pathologies.

Dendritic spines are lost in clusters in Alzheimer\u2019s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a deterioration of neuronal connectivity. The pathological accumulation of tau in neurons is one of the hallmarks of AD and has been connected to the loss of dendritic spines of pyramidal cells, which are the major targets of cortical excitatory synapses and key elements in memory storage. However, the detailed mechanisms underlying the loss of dendritic spines in individuals with AD are still unclear. Here, we used graph-theory approaches to compare the distribution of dendritic spines from neurons with and without tau pathology of AD individuals. We found that the presence of tau pathology determines the loss of dendritic spines in clusters, ruling out alternative models where spine loss occurs at random locations. Since memory storage has been associated with synaptic clusters, the present results provide a new insight into the mechanisms by which tau drives synaptic damage in AD, paving the way to memory deficits through alterations of spine organization.

Neuropathologic basis of frontotemporal dementia in progressive supranuclear palsy.

BackgroundProgressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by neuronal loss in the extrapyramidal system with pathologic accumulation of tau in neurons and glia. The most common clinical presentation of PSP, referred to as Richardson syndrome, is that of atypical parkinsonism with vertical gaze palsy, axial rigidity, and frequent falls. Although cognitive deficits in PSP are often ascribed to subcortical dysfunction, a subset of patients has dementia with behavioral features similar to the behavioral variant of frontotemporal dementia. In this study we aimed to identify the clinical and pathological characteristics of PSP presenting with frontotemporal dementia.MethodsIn this study, we compared clinical and pathologic characteristics of 31 patients with PSP with Richardson syndrome with 15 patients with PSP with frontotemporal dementia. For pathological analysis, we used semiquantitative methods to assess neuronal and glial lesions with tau immunohistochemistry, as well image analysis of tau burden using digital microscopic methods.ResultsWe found greater frontal and temporal neocortical neuronal tau pathology in PSP with frontotemporal dementia compared with PSP with Richardson syndrome. White matter tau pathology was also greater in PSP with frontotemporal dementia than PSP with Richardson syndrome. Genetic and demographic factors were not associated with atypical distribution of tau pathology in PSP with frontotemporal dementia.ConclusionsThe results confirm the subset of cognitive‐predominant PSP mimicking frontotemporal dementia in PSP. PSP with frontotemporal dementia has distinct clinical features that differ from PSP with Richardson syndrome, as well as differences in distribution and density of tau pathology. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Microglial Activation During Pathogenesis of Tauopathy in rTg4510 Mice: Implications for the Early Diagnosis of Tauopathy.

Tauopathy is characterized by the fibrillar tau accumulation in neurons and glial cells. In order to advance our understanding of the causative mechanisms of tauopathy, neuroinflammation, which has been suggested to play important roles in disease progression, will require particular attention. Neuroinflammation is characterized predominantly by microglial activation. At present, it is still under debate whether microglial activation is a cause or a result of neurodegeneration. To search for a temporal relationship between neurodegeneration and neuroinflammation, our group demonstrated that in vivo imaging (e.g., tau-PET, TSPO-PET, and volumetric MRI) of tauopathy mice strongly supports the evidence of microglial activation along with both pathological tau accumulation and brain atrophy. Both in vivo imaging and histochemical analysis confirmed that microglial TSPO accumulation was the late event during the pathogenesis of tauopathy. On the other hand, it is known that purinergic receptor P2Y12 as a marker of homeostatic microglia cells was reduced at an early stage of disease progression. In this review, we will introduce a phenotypic change of microglia in a mouse model of tauopathy and propose novel approaches to the establishment of imaging biomarkers, thereby targeting the early diagnosis of tauopathy.

Current Advances on Different Kinases Involved in Tau Phosphorylation, and Implications in Alzheimers Disease and Tauopathies

Hyperphosphorylation and accumulation of tau in neurons (and glial cells) is one the main pathologic hallmarks in Alzheimer's disease (AD) and other tauopathies, including Pick's disease (PiD), progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease and familial frontotemporal dementia and parkinsonism linked to chromosome 17 due to mutations in the tau gene (FTDP-17-tau). Hyperphosphorylation of tau is regulated by several kinases that phosphorylate specific sites of tau in vitro. GSK-3-immunoprecipitated sarcosyl-insoluble fractions in AD have the capacity to phosphorylate recombinant tau. In addition, GSK-3 phosphorylated at Ser9, that inactivates GSK-3, is found in the majority of neurons with neurofibrillary tangles and dystrophic neurites of senile plaques in AD, and in Pick bodies and other phospho-tau-containing neurons and glial cells in other tauopathies. Increased expression of active kinases, including stress-activated kinase, c-Jun N-terminal kinase (SAPK/JNK) and kinase p38 has been found in brain homogenates in all the tauopathies. Strong active SAPK/JNK and p38 immunoreactivity has been observed restricted to neurons and glial cells containing hyperphosphorylated tau, as well as in dystrophic neurites of senile plaques in AD. Moreover, SAPK/JNK- and p38-immunoprecipitated sub-cellular fractions enriched in abnormal hyperphosphorylated tau have the capacity to phosphorylate recombinant tau and c-Jun and ATF-2 which are specific substrates of SAPK/JNK and p38 in AD and PiD. Interestingly, increased expression of phosphorylated (active) SAPK/JNK and p38 and hyperphosphorylated tau containing neurites have been observed around betaA4 amyloid deposits in the brain of transgenic mice (Tg 2576) carrying the double APP Swedish mutation. These findings suggest that betaA4 amyloid has the capacity to trigger the activation of stress kinases which, in turn, phosphorylate tau in neurites surrounding amyloid deposits. Complementary findings have been reported from the autopsy of two AD patients who participated in an amyloid-beta immunization trial and died during the course of immunization-induced encephalitis. The neuropathological examination of the brain showed massive focal reduction of amyloid plaques but not of neurofibrillary degeneration. Activation of SAPK/JNK and p38 were reduced together with decreased tau hyperphosphorylation of aberrant neurites in association with decreased amyloid plaques in both Tg2576 mice and human brains. These findings support the amyloid cascade hypothesis of tau phosphorylation mediated by stress kinases in dystrophic neurites of senile plaques but not that of neurofibrillary tangles and neuropil threads in AD.

Stress kinases involved in tau phosphorylation in Alzheimer's disease, tauopathies and APP transgenic mice.

Hyperphosphorylation and accumulation of tau in neurons (and glial cells) is one of the main pathologic hallmarks in Alzheimer's disease (AD) and other tauopathies, including Pick's disease (PiD), progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease and familial frontotemporal dementia and parkinsonism linked to chromosome 17 due to mutations in the tau gene (FTDP-17-tau). Recent studies have shown increased expression of select active kinases, including stress-activated kinase, c-Jun N-terminal kinase (SAPK/JNK) and kinase p38 in brain homogenates in all the tauopathies. Strong active SAPK/JNK and p38 immunoreactivity has been observed restricted to neurons and glial cells containing hyperphosphorylated tau, as well as in dystrophic neurites of senile plaques in AD. Moreover, SAPK/JNK- and p38-immunoprecipitated sub-cellular fractions enriched in abnormal hyperphosphorylated tau have the capacity to phosphorylate recombinat tau and c-Jun and ATF-2 which are specific substrates of SAPK/JNK and p38 in AD and PiD. Interestingly, increased expression of phosphorylated SAPK/JNK and p38 in association with hyperphosphorylated tau containing neurites have been observed around betaA4 amyloid deposits in the brain of transgenic mice (Tg2576)carrying the double APP Swedish mutation. These findings suggest that betaA4 amyloid has the capacity to trigger the activation of stress kinases which, in turn, phosphorylate tau in neurites surrounding amyloid deposits. Reduction in the amyloid burden and decreased numbers of amyloid plaques but not of neurofibrillary degeneration has been observed in the brain of two AD patients who participated in an amyloid-beta immunization trial. Activation of stress kinases SAPK/JNK and p38 were reduced together with decreased tau hyperphosphorylation of aberrant neurites in association with decreased amyloid plaques. These findings support the amyloid cascade hypothesis of tau phosphorylation mediated by stress kinases in dystrophic neurites of senile plaques but not that of neurofibrillary tangles and neuropil threads in AD.

Study of Alzheimer's disease using transgenic mice: The mechanism of formation of brain Aβ amyloid and neurofibrillary tangles

Background: The purpose of the present paper was to clarify the role of brain amyloid β protein (Aβ) in Alzheimer's disease (AD) with the eventual aim of developing new treatments.Methods: Three kinds of transgenic mice (Tg) were examined: those overexpressing βAPP695ΔNL (APPsw mice), those expressing the R406W mutant form of human 4‐repeat tau (tauR406W mice), and those with both βAPP695ΔNL and R406W mutant tau (APPsw × tau R406 double Tg).Results: First, cored plaques, diffuse plaques and amyloid angiopathy were detected in the brains of APPsw mice. Loss of neurons and synapses was seen in the cored plaques, and accumulation of phosphorylated‐tau in dystrophic neurites around the cored plaques. However, Neurofibrillary tangles were not seen. These mice displayed memory impairment and decreased levels of acetylcholine in the cortex and hippocampus. Second, tau R406W mice were produced. These mice developed motor disturbances and memory impairment, accompanied by gliosis and marked tau accumulation in neurons of the frontotemporal cortex, hippocampus and amygdala. No Aβ was detected. Third, APPsw × tauR406W double Tg were produced. The pattern of Aβ deposition was similar in these double Tg and the APPsw mice. Gallyas silver‐staining showed greater levels of tauopathy in the hippocampus in these double Tg compared to the tauR406W mice.Conclusion: These findings suggest that deposition of brain Aβ is the initial event leading to subsequent disease such as accumulation of phosphorylated tau, neuronal loss and memory disturbance, and that the treatment of brain Aβ should be the first priority in finding a cure for AD.

Dementia with Lewy bodies from the perspective of tauopathy.

We immunohistochemically investigated the prevalence and pattern of phosphorylated tau accumulation in neurons and glia in 46 cases of dementia with Lewy bodies (DLB). Tau-positive neurons composed of neurofibrillary tangles (NFT) and pretangle neurons were found in the hippocampal area in all 46 cases, although the ratio of pretangle neurons in tau-positive neurons was higher in the cases showing low NFT stages. Tau-positive astrocytes were found in the periventricular area in 18 of 46 cases, and partly represented argyrophilic thorn-shaped astrocytes. In contrast, tau-positive oligodendroglia were found in the subcortical white matter in 9 of 46 cases, and represented argyrophilic coiled bodies. Tau-positive argyrophilic grains were found in the hippocampal area in the same cases as those with coiled bodies. The 9 cases with tau-positive coiled bodies and grains were included in the 18 cases with tau-positive astrocytes, and showed larger proportions in the low NFT stages than the 46 cases with tau-positive neurons. Tau-positive neurons were positive both to anti-three-repeat (3R) and -4R tau-specific antibodies, while tau-positive astrocytes, coiled bodies and grains were predominantly positive to anti-4R tau-specific antibody. These tau-positive structures were negative to anti-alpha-synuclein antibody. These findings suggest that the tau accumulation in DLB represents both tau-positive neurons with all six tau isoforms and tau-positive astrocytes, coiled bodies and grains with the 4R tau isoform, and that the different cytoskeletal abnormalities form a link between some neurodegenerative dementing disorders including DLB.