scholarly journals Quantitative propagation of assembled human Tau from Alzheimer's disease brain in microfluidic neuronal cultures

2020 ◽  
Vol 295 (37) ◽  
pp. 13079-13093 ◽  
Author(s):  
Antigoni Katsikoudi ◽  
Elena Ficulle ◽  
Annalisa Cavallini ◽  
Gary Sharman ◽  
Amelie Guyot ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Imaging Techniques ◽  
Therapeutic Interventions ◽  
Neuronal Cultures ◽  
Tau Pathology ◽  
High Content Imaging ◽  
Molecule Inhibitor ◽  
Culture Model ◽  
Tau Aggregation

Tau aggregation and hyperphosphorylation is a key neuropathological hallmark of Alzheimer's disease (AD), and the temporospatial spread of Tau observed during clinical manifestation suggests that Tau pathology may spread along the axonal network and propagate between synaptically connected neurons. Here, we have developed a cellular model that allows the study of human AD-derived Tau propagation from neuron to neuron using microfluidic devices. We show by using high-content imaging techniques and an in-house developed interactive computer program that human AD-derived Tau seeds rodent Tau that propagates trans-neuronally in a quantifiable manner in a microfluidic culture model. Moreover, we were able to convert this model to a medium-throughput format allowing the user to handle 16 two-chamber devices simultaneously in the footprint of a standard 96-well plate. Furthermore, we show that a small molecule inhibitor of aggregation can block the trans-neuronal transfer of Tau aggregates, suggesting that the system can be used to evaluate mechanisms of Tau transfer and find therapeutic interventions.

scholarly journals Alzheimer’s disease brain contains tau fractions with differential prion-like activities

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Longfei Li ◽  
Ruirui Shi ◽  
Jianlan Gu ◽  
Yunn Chyn Tung ◽  
Yan Zhou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cultured Cells ◽  
Regional Distribution ◽  
Proteinase K ◽  
Hyperphosphorylated Tau ◽  
Terminal Portion ◽  
Tau Pathology ◽  
Heat Stable ◽  
Tau Aggregation

AbstractNeurofibrillary tangles (NFTs) made of abnormally hyperphosphorylated tau are a hallmark of Alzheimer’s disease (AD) and related tauopathies. Regional distribution of NFTs is associated with the progression of the disease and has been proposed to be a result of prion-like propagation of misfolded tau. Tau in AD brain is heterogenous and presents in various forms. In the present study, we prepared different tau fractions by sedimentation combined with sarkosyl solubility from AD brains and analyzed their biochemical and pathological properties. We found that tau in oligomeric fraction (O-tau), sarkosyl-insoluble fractions 1 and 2 (SI1-tau and SI2-tau) and monomeric heat-stable fraction (HS-tau) showed differences in truncation, hyperphosphorylation, and resistance to proteinase K. O-tau, SI1-tau, and SI2-tau, but not HS-tau, were hyperphosphorylated at multiple sites and contained SDS- and β-mercaptoethanol–resistant high molecular weight aggregates, which lacked the N-terminal portion of tau. O-tau and SI2-tau displayed more truncation and less hyperphosphorylation than SI1-tau. Resistance to proteinase K was increased from O-tau to SI1-tau to SI2-tau. O-tau and SI1-tau, but not SI2-tau or HS-tau, captured tau from cell lysates and seeded tau aggregation in cultured cells. Heat treatment could not kill the prion-like activity of O-tau to capture normal tau. Hippocampal injection of O-tau into 18-month-old FVB mice induced significant tau aggregation in both ipsilateral and contralateral hippocampi, but SI1-tau only induced tau pathology in the ipsilateral hippocampus, and SI2-tau and HS-tau failed to induce any detectable tau aggregation. These findings suggest that O-tau and SI1-tau have prion-like activities and may serve as seeds to recruit tau and template tau to aggregate, resulting in the propagation of tau pathology. Heterogeneity of tau pathology within AD brain results in different fractions with different biological and prion-like properties, which may pose a major challenge in targeting tau for development of effective therapeutic treatments.

scholarly journals Microglia in Alzheimer’s Disease: A Target for Therapeutic Intervention

2021 ◽  
Vol 15 ◽  
Author(s):  
Guimei Zhang ◽  
Zicheng Wang ◽  
Huiling Hu ◽  
Meng Zhao ◽  
Li Sun
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Interventions ◽  
Tau Pathology ◽  
Age Related ◽  
Amyloid Accumulation ◽  
Pathophysiological Role ◽  
Inflammatory Drugs ◽  
Β Amyloid

Alzheimer’s disease (AD) is one of the most common types of age-related dementia worldwide. In addition to extracellular amyloid plaques and intracellular neurofibrillary tangles, dysregulated microglia also play deleterious roles in the AD pathogenesis. Numerous studies have demonstrated that unbridled microglial activity induces a chronic neuroinflammatory environment, promotes β-amyloid accumulation and tau pathology, and impairs microglia-associated mitophagy. Thus, targeting microglia may pave the way for new therapeutic interventions. This review provides a thorough overview of the pathophysiological role of the microglia in AD and illustrates the potential avenues for microglia-targeted therapies, including microglial modification, immunoreceptors, and anti-inflammatory drugs.

scholarly journals Astrocytic expression of the Alzheimer’s disease risk allele, ApoEε4, potentiates neuronal tau pathology in multiple preclinical models

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Angela Marie Jablonski ◽  
Lee Warren ◽  
Marija Usenovic ◽  
Heather Zhou ◽  
Jonathan Sugam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Risk ◽  
In Vitro Models ◽  
Tau Pathology ◽  
Adeno Associated Virus ◽  
Human Apoe ◽  
Specific Effects ◽  
Tau Aggregation

AbstractApoEε4 is a major genetic risk factor for Alzheimer’s disease (AD), a disease hallmarked by extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). The presence of the ApoEε4 allele is associated with increased Aβ deposition and a role for ApoEε4 in the potentiation of tau pathology has recently emerged. This study focused on comparing the effects of adeno-associated virus (AAV)-mediated overexpression of the three predominant human ApoE isoforms within astrocytes. The isoform-specific effects of human ApoE were evaluated within in vitro models of tau pathology within neuron/astrocyte co-cultures, as well as in a transgenic tau mouse model. Tau aggregation, accumulation, and phosphorylation were measured to determine if the three isoforms of human ApoE had differential effects on tau. Astrocytic overexpression of the human ApoEε4 allele increased phosphorylation and misfolding of overexpressed neuronal tau in multiple models, including the aggregation and accumulation of added tau oligomers, in an isoform-specific manner. The ability of ApoEε4 to increase tau aggregation could be inhibited by an ApoEε4-specific antibody. This study indicates that astrocytic expression of ApoEε4 can potentiate tau aggregation and phosphorylation within neurons and supports a gain of toxic function hypothesis for the effect of hApoEε4 on tau.

scholarly journals Ageing and amyloidosis underlie the molecular and pathological alterations of tau in a mouse model of familial Alzheimer’s disease

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Athanasios Metaxas ◽  
Camilla Thygesen ◽  
Stefan J. Kempf ◽  
Marco Anzalone ◽  
Ramanan Vaitheeswaran ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Subjects ◽  
Experimental Models ◽  
Mouse Tissue ◽  
Tau Pathology ◽  
Cerebral Amyloidosis ◽  
Necessary And Sufficient ◽  
Tau Aggregation ◽  
Tau Aggregate

Abstract Despite compelling evidence that the accumulation of amyloid-beta (Aβ) promotes neocortical MAPT (tau) aggregation in familial and idiopathic Alzheimer’s disease (AD), murine models of cerebral amyloidosis are not considered to develop tau-associated pathology. In the present study, we show that tau can accumulate spontaneously in aged transgenic APPswe/PS1ΔE9 mice. Tau pathology is abundant around Aβ deposits, and further characterized by accumulation of Gallyas and thioflavin-S-positive inclusions, which were detected in the APPswe/PS1ΔE9 brain at 18 months of age. Age-dependent increases in argyrophilia correlated positively with binding levels of the paired helical filament (PHF) tracer [18F]Flortaucipir, in all brain areas examined. Sarkosyl-insoluble PHFs were visualized by electron microscopy. Quantitative proteomics identified sequences of hyperphosphorylated and three-repeat tau in transgenic mice, along with signs of RNA missplicing, ribosomal dysregulation and disturbed energy metabolism. Tissue from the frontal gyrus of human subjects was used to validate these findings, revealing primarily quantitative differences between the tau pathology observed in AD patient vs. transgenic mouse tissue. As physiological levels of endogenous, ‘wild-type’ tau aggregate secondarily to Aβ in APPswe/PS1ΔE9 mice, this study suggests that amyloidosis is both necessary and sufficient to drive tauopathy in experimental models of familial AD.

scholarly journals Delta-secretase cleavage of Tau mediates its pathology and propagation in Alzheimer’s disease

2020 ◽  
Vol 52 (8) ◽  
pp. 1275-1287
Author(s):  
Seong Su Kang ◽  
Eun Hee Ahn ◽  
Keqiang Ye
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Strategy ◽  
Senile Plaques ◽  
Tau Pathology ◽  
Disease Modifying ◽  
Tau Aggregation ◽  
The Brain ◽  
Insight Into

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease with age as a major risk factor. AD is the most common dementia with abnormal structures, including extracellular senile plaques and intraneuronal neurofibrillary tangles, as key neuropathologic hallmarks. The early feature of AD pathology is degeneration of the locus coeruleus (LC), which is the main source of norepinephrine (NE) supplying various cortical and subcortical areas that are affected in AD. The spread of Tau deposits is first initiated in the LC and is transported in a stepwise manner from the entorhinal cortex to the hippocampus and then to associative regions of the neocortex as the disease progresses. Most recently, we reported that the NE metabolite DOPEGAL activates delta-secretase (AEP, asparagine endopeptidase) and triggers pathological Tau aggregation in the LC, providing molecular insight into why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in the disease and how δ-secretase mediates the spread of Tau pathology to the rest of the brain. This review summarizes our current understanding of the crucial role of δ-secretase in driving and spreading AD pathologies by cleaving multiple critical players, including APP and Tau, supporting that blockade of δ-secretase may provide an innovative disease-modifying therapeutic strategy for treating AD.

scholarly journals A Closer Look into the Role of Protein Tau in the Identification of Promising Therapeutic Targets for Alzheimer’s Disease

2018 ◽  
Vol 8 (9) ◽  
pp. 162 ◽  
Author(s):  
Rubayat Islam Khan ◽  
Saif Nirzhor ◽  
Barnaly Rashid
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Tau Protein ◽  
Imaging Techniques ◽  
Memory Loss ◽  
Amyloid Β ◽  
Full Time ◽  
Tau Pathology ◽  
Severe Change

One of the most commonly known chronic neurodegenerative disorders, Alzheimer’s disease (AD), manifests the common type of dementia in 60–80% of cases. From a clinical standpoint, a patent cognitive decline and a severe change in personality, as caused by a loss of neurons, is usually evident in AD with about 50 million people affected in 2016. The disease progression in patients is distinguished by a gradual plummet in cognitive functions, eliciting symptoms such as memory loss, and eventually requiring full-time medical care. From a histopathological standpoint, the defining characteristics are intracellular aggregations of hyper-phosphorylated tau protein, known as neurofibrillary tangles (NFT), and depositions of amyloid β-peptides (Aβ) in the brain. The abnormal phosphorylation of tau protein is attributed to a wide gamut of neurological disorders known as tauopathies. In addition to the hyperphosphorylated tau lesions, neuroinflammatory processes could occur in a sustained manner through astro-glial activation, resulting in the disease progression. Recent findings have suggested a strong interplay between the mechanism of Tau phosphorylation, disruption of microtubules, and synaptic loss and pathology of AD. The mechanisms underlying these interactions along with their respective consequences in Tau pathology are still ill-defined. Thus, in this review: (1) we highlight the interplays existing between Tau pathology and AD; and (2) take a closer look into its role while identifying some promising therapeutic advances including state of the art imaging techniques.

scholarly journals Acetylation of Tau Induces Alzheimer's Disease-Associated Tau in Transgenic Mice

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 966-966
Author(s):  
Addison Ali ◽  
Kristeen Pareja ◽  
Tara Tracy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Neurodegenerative Disorder ◽  
Mossy Fibers ◽  
Tau Proteins ◽  
Phosphorylated Tau ◽  
Tau Pathology ◽  
Ca1 Region ◽  
Tau Aggregation

Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by neurofibrillary tangles (NFTs) and amyloid beta plaques. These NFTs are made up of aggregated tau proteins. Tau is involved in stabilizing microtubules and does not usually display aggregation. Acetylation of tau protein causes an increase in tau aggregation but its role in AD progression is still not well understood. I hypothesized that enhanced acetylated tau results in an increase in AD-like tau pathology. To test this, a murine prion promoter-tauKQ transgene was injected into the mouse fertilized oocyte. The tauKQ mutation alters lysine to glutamine to mimic acetylation of tau. Nontransgenic mice were used as controls. AT8 and GT-38 antibodies were used in immunohistochemistry (IHC) to target phosphorylated tau and AD-associated tau, respectively. GT-38 is conformation-dependent and requires 3R and 4R tau isoforms which makes it specific to AD. Through immunofluorescence, increased phosphorylated tau was observed in the hippocampus of the tauKQ mice compared to the nontransgenic mice. I focused on the dentate gyrus, CA1 region, and the mossy fibers of the CA3 region since they are involved in many memory processes. Through chromogenic IHC, the tauKQ mice exhibited more 3R+4R tau isoform pathology in the mossy fibers than the nontransgenic mice. This data suggests that an acetylation mimic is sufficient to stimulate an abundance of AD-related tau pathology in transgenic mice which is consistent with my hypothesis. The tauKQ mouse model can assist in understanding the role of tau acetylation and tau progression for AD.

scholarly journals Tau AD fragment aggregates proliferate through autocatalytic secondary nucleation

2021 ◽  
Author(s):  
Diana Rodriguez Camargo ◽  
Eimantas Sileikis ◽  
Sean Chia ◽  
Emil Axell ◽  
Katja Bernfur ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Self Assembly ◽  
Isotope Composition ◽  
Therapeutic Interventions ◽  
Secondary Nucleation ◽  
Kinetic Measurements ◽  
Primary Nucleation ◽  
Tau Aggregation

Abstract The self-assembly of the protein tau into neurofibrillary tangles is one of the hallmarks of Alzheimer’s disease and related tauopathies. Still, the molecular mechanism of tau aggregation is largely unknown. This problem may be addressed by systematically obtaining reproducible in vitro kinetic measurements under quiescent conditions in the absence of triggering substances. Here, we implement this strategy by developing protocols for obtaining an ultra-pure tau fragment (residues 304-380 of tau441, tau AD fragment) and for performing spontaneous aggregation assays with reproducible kinetics under quiescent conditions. We are thus able to identify the mechanism of fibril formation of the tau AD fragment at physiological pH using fluorescence spectroscopy and mass spectrometry. We find that primary nucleation is slow, and that secondary processes dominate the aggregation process once the initial aggregates are formed. Moreover, our results further show that secondary nucleation of monomers on fibril surfaces dominate over fragmentation of fibrils. Using separate isotopes in monomers and fibrils, through mass spectroscopy measurements, we verify the isotope composition of the intermediate oligomeric species, which reveals that these small aggregates are generated from monomer through secondary nucleation. Our results provide a framework for understanding the processes leading to tau aggregation in disease, and for selecting possible tau forms as targets in the development of therapeutic interventions in Alzheimer’s disease.

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