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

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.

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AADVAC1, AN ACTIVE IMMUNOTHERAPY FOR ALZHEIMER’S DISEASE AND NON ALZHEIMER TAUOPATHIES: AN OVERVIEW OF PRECLINICAL AND CLINICAL DEVELOPMENT

Journal of Prevention of Alzheimer's Disease ◽

10.14283/jpad.2018.45 ◽

2018 ◽

pp. 1-7

Author(s):

P. Novak ◽

N. Zilka ◽

M. Zilkova ◽

B. Kovacech ◽

R. Skrabana ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Tau Protein ◽

Neurodegenerative Disorder ◽

Therapeutic Potential ◽

Phase 1 ◽

Primary Progressive Aphasia ◽

Tau Proteins ◽

Active Immunotherapy ◽

Tau Pathology

Neurofibrillary tau protein pathology is closely associated with the progression and phenotype of cognitive decline in Alzheimer’s disease and other tauopathies, and a high-priority target for disease-modifying therapies. Herein, we provide an overview of the development of AADvac1, an active immunotherapy against tau pathology, and tau epitopes that are potential targets for immunotherapy. The vaccine leads to the production of antibodies that target conformational epitopes in the microtubule-binding region of tau, with the aim to prevent tau aggregation and spreading of pathology, and promote tau clearance. The therapeutic potential of the vaccine was evaluated in transgenic rats and mice expressing truncated, non mutant tau protein, which faithfully replicate of human tau pathology. Treatment with AADvac1 resulted in reduction of neurofibrillary pathology and insoluble tau in their brains, and amelioration of their deleterious phenotype. The vaccine was highly immunogenic in humans, inducing production of IgG antibodies against the tau peptide in 29/30 treated elderly patients with mild-to-moderate Alzheimer’s. These antibodies were able to recognise insoluble tau proteins in Alzheimer patients’ brains. Treatment with AADvac1 proved to be remarkably safe, with injection site reactions being the only adverse event tied to treatment. AADvac1 is currently being investigated in a phase 2 study in Alzheimer’s disease, and a phase 1 study in non-fluent primary progressive aphasia, a neurodegenerative disorder with a high tau pathology component.

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Correction to: Norovirus P particle-based tau vaccine-generated phosphorylated tau antibodies markedly ameliorate tau pathology and improve behavioral deficits in mouse model of Alzheimer’s disease

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00657-6 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Yao Sun ◽

Yongqing Guo ◽

Xuejian Feng ◽

Lu Fu ◽

Yayuan Zheng ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Phosphorylated Tau ◽

Tau Pathology ◽

Behavioral Deficits ◽

Model Of Alzheimer’S Disease

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“Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies

Molecular Neurodegeneration ◽

10.1186/s13024-021-00460-5 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Yuxing Xia ◽

Stefan Prokop ◽

Benoit I. Giasson

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Kinase Inhibitors ◽

Tau Phosphorylation ◽

Phosphorylated Tau ◽

Clinical Biomarkers ◽

Early Results ◽

Recent Developments ◽

Tau Aggregation

AbstractPhosphorylation is one of the most prevalent post-translational modifications found in aggregated tau isolated from Alzheimer’s disease (AD) patient brains. In tauopathies like AD, increased phosphorylation or hyperphosphorylation can contribute to microtubule dysfunction and is associated with tau aggregation. In this review, we provide an overview of the structure and functions of tau protein as well as the physiologic roles of tau phosphorylation. We also extensively survey tau phosphorylation sites identified in brain tissue and cerebrospinal fluid from AD patients compared to age-matched healthy controls, which may serve as disease-specific biomarkers. Recently, new assays have been developed to measure minute amounts of specific forms of phosphorylated tau in both cerebrospinal fluid and plasma, which could potentially be useful for aiding clinical diagnosis and monitoring disease progression. Additionally, multiple therapies targeting phosphorylated tau are in various stages of clinical trials including kinase inhibitors, phosphatase activators, and tau immunotherapy. With promising early results, therapies that target phosphorylated tau could be useful at slowing tau hyperphosphorylation and aggregation in AD and other tauopathies.

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

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01127-4 ◽

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.

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Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease

Science Advances ◽

10.1126/sciadv.aaz2387 ◽

2020 ◽

Vol 6 (16) ◽

pp. eaaz2387 ◽

Cited By ~ 18

Author(s):

Niklas Mattsson-Carlgren ◽

Emelie Andersson ◽

Shorena Janelidze ◽

Rik Ossenkoppele ◽

Philip Insel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Pet ◽

Phosphorylated Tau ◽

Positron Emission ◽

Aβ Aggregation ◽

Tau Pet ◽

5Xfad Mice ◽

Tau Aggregation ◽

T Tau

The links between β-amyloid (Aβ) and tau in Alzheimer’s disease are unclear. Cognitively unimpaired persons with signs of Aβ pathology had increased cerebrospinal fluid (CSF) phosphorylated tau (P-tau181 and P-tau217) and total-tau (T-tau), which increased over time, despite no detection of insoluble tau aggregates [normal Tau positron emission tomography (PET)]. CSF P-tau and T-tau started to increase before the threshold for Amyloid PET positivity, while Tau PET started to increase after Amyloid PET positivity. Effects of Amyloid PET on Tau PET were mediated by CSF P-tau, and high CSF P-tau predicted increased Tau PET rates. Individuals with MAPT mutations and signs of tau deposition (but without Aβ pathology) had normal CSF P-tau levels. In 5xFAD mice, CSF tau increased when Aβ aggregation started. These results show that Aβ pathology may induce changes in soluble tau release and phosphorylation, which is followed by tau aggregation several years later in humans.

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Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains

Acta Neuropathologica ◽

10.1007/s00401-014-1373-0 ◽

2014 ◽

Vol 129 (2) ◽

pp. 221-237 ◽

Cited By ~ 114

Author(s):

Susana Boluda ◽

Michiyo Iba ◽

Bin Zhang ◽

Kevin M. Raible ◽

Virginia M-Y. Lee ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Corticobasal Degeneration ◽

Tau Pathology ◽

Differential Induction

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Searching for novel cerebrospinal fluid biomarkers of tau pathology in frontotemporal dementia: an elusive quest

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-319266 ◽

2019 ◽

Vol 90 (7) ◽

pp. 740-746 ◽

Cited By ~ 7

Author(s):

Martha S Foiani ◽

Claudia Cicognola ◽

Natalia Ermann ◽

Ione O C Woollacott ◽

Carolin Heller ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Frontotemporal Dementia ◽

Neurodegenerative Disorder ◽

The Novel ◽

Tau Pathology ◽

Total Tau ◽

Significant Difference ◽

T Tau

BackgroundFrontotemporal dementia (FTD) is a pathologically heterogeneous neurodegenerative disorder associated usually with tau or TDP-43 pathology, although some phenotypes such as logopenic variant primary progressive aphasia are more commonly associated with Alzheimer’s disease pathology. Currently, there are no biomarkers able to diagnose the underlying pathology during life. In this study, we aimed to investigate the potential of novel tau species within cerebrospinal fluid (CSF) as biomarkers for tau pathology in FTD.Methods86 participants were included: 66 with a clinical diagnosis within the FTD spectrum and 20 healthy controls. Immunoassays targeting tau fragments N-123, N-mid-region, N-224 and X-368, as well as a non-phosphorylated form of tau were measured in CSF, along with total-tau (T-tau) and phospho-tau (P-tau(181)). Patients with FTD were grouped based on their Aβ42 level into those likely to have underlying Alzheimer’s disease (AD) pathology (n=21) and those with likely frontotemporal lobar degeneration (FTLD) pathology (n=45). The FTLD group was then subgrouped based on their underlying clinical and genetic diagnoses into those with likely tau (n=7) or TDP-43 (n=18) pathology.ResultsSignificantly higher concentrations of tau N-mid-region, tau N-224 and non-phosphorylated tau were seen in both the AD group and FTLD group compared with controls. However, none of the novel tau species showed a significant difference between the AD and FTLD groups, nor between the TDP-43 and tau pathology groups. In a subanalysis, normalising for total-tau, none of the novel tau species provided a higher sensitivity and specificity to distinguish between tau and TDP-43 pathology than P-tau(181)/T-tau, which itself only had a sensitivity of 61.1% and specificity of 85.7% with a cut-off of <0.109.ConclusionsDespite investigating multiple novel CSF tau fragments, none show promise as an FTD biomarker and so the quest for in vivo markers of FTLD-tau pathology continues.

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Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota

Scientific Reports ◽

10.1038/srep41802 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 209

Author(s):

T. Harach ◽

N. Marungruang ◽

N. Duthilleul ◽

V. Cheatham ◽

K. D. Mc Coy ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Microbiota ◽

Transgenic Mice ◽

Intestinal Microbiota ◽

Neurodegenerative Disorder ◽

Wild Type ◽

Germ Free ◽

Amyloid Pathology ◽

Aβ Amyloid

Abstract Alzheimer’s disease is the most common form of dementia in the western world, however there is no cure available for this devastating neurodegenerative disorder. Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer’s disease is not known. To this end we sequenced bacterial 16S rRNA from fecal samples of Aβ precursor protein (APP) transgenic mouse model and found a remarkable shift in the gut microbiota as compared to non-transgenic wild-type mice. Subsequently we generated germ-free APP transgenic mice and found a drastic reduction of cerebral Aβ amyloid pathology when compared to control mice with intestinal microbiota. Importantly, colonization of germ-free APP transgenic mice with microbiota from conventionally-raised APP transgenic mice increased cerebral Aβ pathology, while colonization with microbiota from wild-type mice was less effective in increasing cerebral Aβ levels. Our results indicate a microbial involvement in the development of Abeta amyloid pathology, and suggest that microbiota may contribute to the development of neurodegenerative diseases.

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