Experimental Models of Tauopathy – From Mechanisms to Therapies

Götz, Julika J.; Götz, Jürgen

doi:10.1007/978-981-32-9358-8_28

Cited by 20 publications

(19 citation statements)

References 90 publications

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“…The presence of motor dysfunction would be a sign of potential toxicity and can confound interpretation of behavioral testing. Some tau only Tg models have motor dysfunction; however, this had not been noted in our hTau/PS1 Tg AD model (Boutajangout et al, 2008;Drummond and Wisniewski, 2017;Götz and Götz, 2019). This model expresses mutated PS1 (M146L) and all human tau isoforms on a murine tau knockout background (hTau/PS1/mTau−/−).…”

Section: Discussionmentioning

confidence: 75%

“…Despite showing success in many AD models immunotherapy targeting Aβ has failed in clinical trials thus far (Reiss et al, 2020;Vaz and Silvestre, 2020). Immunotherapy addressing tau pathology has been less extensively investigated, but may represent a better target, since this pathology correlates better with AD cognitive symptoms (Nelson et al, 2012;Götz and Götz, 2019;Plotkin and Cashman, 2020;Soeda and Takashima, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Tau pathology targeted immunotherapy is a less explored area of investigation compared to Aβ targeted approaches; however, it is a very active area of study with two trials of active immunization and ten on-going passive immunization trials (Götz and Götz, 2019;Plotkin and Cashman, 2020;Soeda and Takashima, 2020;Vander Zanden and Chi, 2020). An important criterion for this approach is that the immune response generated must avoid interacting with native, monomeric tau in neurons; hence, the majority of the anti-tau antibodies being tested are more specific to aggregated, oligomeric tau species (Plotkin and Cashman, 2020;Soeda and Takashima, 2020;Vander Zanden and Chi, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Hence it has been proposed that the inhibition of oligomer mediated toxicity by immunotherapy is the most likely approach to be clinically successful, for AD and other neurodegenerative disorders (Wisniewski and Goñi, 2015;Herline et al, 2018a). Tau targeted immunotherapies are currently also being developed; however, less effort has been directed on interventions targeting tau pathology compared to Aβ (Li and Götz, 2017;Götz and Götz, 2019;Kwon et al, 2020;Vaz and Silvestre, 2020). In the present study, we aimed to test a novel immunotherapeutic approach's ability to ameliorate tau-related pathology by blocking oligomer mediated toxicity, using an AD transgenic (Tg) model, which we developed (Boutajangout et al, 2008(Boutajangout et al, , 2009(Boutajangout et al, , 2010.…”

Section: Introductionmentioning

confidence: 99%

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Passive Immunization With a Novel Monoclonal Anti-PrP Antibody TW1 in an Alzheimer’s Mouse Model With Tau Pathology

Boutajangout

Zhang

Kim

et al. 2021

Front. Aging Neurosci.

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Neurofibrillary tangles (NFTs) are a major pathologic hallmark of Alzheimer’s disease (AD). Several studies have shown that amyloid β oligomers (Aβo) and tau oligomers mediate their toxicity, in part, via binding to cellular prion protein (PrPC) and that some anti-PrP antibodies can block this interaction. We have generated a novel monoclonal anti-PrP antibody (TW1) and assessed the efficacy of passive immunization with it in a mouse model of AD with extensive tau pathology: hTau/PS1 transgenic (Tg) mice. These mice were injected intraperitoneally once a week with TW1 starting at 5 months of age. Behavior was assessed at 8 months of age and brain tissue was subsequently harvested for analysis of treatment efficacy at 9 months. Mice treated with TW1 did not show any significant difference in sensorimotor testing including traverse beam, rotarod, and locomotor activity compared to controls. Significant cognitive benefits were observed with the novel object recognition test (ORT) in the immunized mice (two-tailed, t-test p = 0.0019). Immunized mice also showed cognitive benefits on the closed field symmetrical maze (day 1 two-tailed t-test p = 0.0001; day 2 two-tailed t-test p = 0.0015; day 3 two-tailed t-test p = 0.0002). Reduction of tau pathology was observed with PHF-1 immunohistochemistry in the piriform cortex by 60% (two-tailed t-test p = 0.01) and in the dentate gyrus by 50% (two-tailed t-test p = 0.02) in animals treated with TW1 compared to controls. There were no significant differences in astrogliosis or microgliosis observed between treated and control mice. As assessed by Western blots using PHF-1, the TW1 therapy reduced phosphorylated tau pathology (two-tailed t-test p = 0.03) and improved the ratio of pathological soluble tau to tubulin (PHF1/tubulin; two-tailed t-test p = 0.0006). Reduction of tau pathology also was observed using the CP13 antibody (two-tailed t-test p = 0.0007). These results indicate that passive immunization with the TW1 antibody can significantly decrease tau pathology as assessed by immunohistochemical and biochemical methods, resulting in improved cognitive function in a tau transgenic mouse model of AD.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Passive Immunization With a Novel Monoclonal Anti-PrP Antibody TW1 in an Alzheimer’s Mouse Model With Tau Pathology

Boutajangout

Zhang

Kim

et al. 2021

Front. Aging Neurosci.

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“…Tauopathies are neurological disorders (Avila et al, 2004;Götz and Götz, 2019), characterized by aberrant tau aggregates (NFT and tau inclusions) in neurons and glial cells. These aggregates represent tau gene mutations or hyperphosphorylated tau (Kovacs, 2015).…”

Section: Tau Protein and Tauopathiesmentioning

confidence: 99%

New Insights Into Drug Discovery Targeting Tau Protein

Soeda

Takashima

2020

Front. Mol. Neurosci.

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Microtubule-associated protein tau is characterized by the fact that it is an intrinsically disordered protein due to its lack of a stable conformation and high flexibility. Intracellular inclusions of fibrillar forms of tau with a β-sheet structure accumulate in the brain of patients with Alzheimer's disease and other tauopathies. Accordingly, detachment of tau from microtubules and transition of tau from a disordered state to an abnormally aggregated state are essential events preceding the onset of tau-related diseases. Many reports have shown that this transition is caused by post-translational modifications, including hyperphosphorylation and acetylation. The misfolded tau is self-assembled and forms a tau oligomer before the appearance of tau inclusions. Animal and pathological studies using human samples have demonstrated that tau oligomer formation contributes to neuronal loss. During the progression of tauopathies, tau seeds are released from cells and incorporated into other cells, leading to the propagation of pathological tau aggregation. Accumulating evidence suggests several potential approaches for blocking tau-mediated toxicity: (1) direct inhibition of pathological tau aggregation and (2) inhibition of tau post-translational modifications that occur prior to pathological tau aggregation, (3) inhibition of tau propagation and (4) stabilization of microtubules. In addition to traditional low-molecular-weight compounds, newer drug discovery approaches such as the development of medium-molecular-weight drugs (peptide- or oligonucleotide-based drugs) and high-molecular-weight drugs (antibody-based drugs) provide alternative pathways to preventing the formation of abnormal tau. Of particular interest are recent studies suggesting that tau droplet formation by liquid-liquid phase separation may be the initial step in aberrant tau aggregation, as well results that implicate roles for tau in dendritic and nuclear functions. Here, we review the mechanisms through which drugs can target tau and consider recent clinical trials for the treatment of tauopathies. In addition, we discuss the utility of these newer strategies and propose future directions for research on tau-targeted therapeutics.

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The unique neuropathological vulnerability of the human brain to aging

Ferrer

2023

Ageing Research Reviews

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Experimental Models of Tauopathy – From Mechanisms to Therapies

Cited by 20 publications

References 90 publications

Passive Immunization With a Novel Monoclonal Anti-PrP Antibody TW1 in an Alzheimer’s Mouse Model With Tau Pathology

Passive Immunization With a Novel Monoclonal Anti-PrP Antibody TW1 in an Alzheimer’s Mouse Model With Tau Pathology

New Insights Into Drug Discovery Targeting Tau Protein

The unique neuropathological vulnerability of the human brain to aging

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