Single domain antibodies targeting pathological tau protein: Influence of four IgG subclasses on efficacy and toxicity

Congdon, Erin E.; Pan, Ruimin; Jiang, Yixiang; Sandusky‐Beltran, Leslie A.; Dodge, Andie; Yang, Lin; Liu, Mengyu; Kuo, Min-Liang; Kong, Xiang‐Peng; Sigurdsson, Einar M.

doi:10.1016/j.ebiom.2022.104249

Cited by 18 publications

(19 citation statements)

References 82 publications

(116 reference statements)

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“…The extent of its brain entry following intravenous injection or its feasibility as a diagnostic imaging probe have not been reported. In addition, we recently reported on the efficacies of two anti-tau sdAbs, including 2B8, in clearing pathological tau and preventing its toxicity in culture and in tg tauopathy mice ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

Single-domain antibody–based noninvasive in vivo imaging of α-synuclein or tau pathology

et al. 2023

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Intracellular deposition of α-synuclein and tau are hallmarks of synucleinopathies and tauopathies, respectively. Recently, several dye-based imaging probes with selectivity for tau aggregates have been developed, but suitable imaging biomarkers for synucleinopathies are still unavailable. Detection of both of these aggregates early in the disease process may allow for prophylactic therapies before functional impairments have manifested, highlighting the importance of developing specific imaging probes for these lesions. In contrast to the β sheet dyes, single-domain antibodies, found in camelids and a few other species, are highly specific, and their small size allows better brain entry and distribution than whole antibodies. Here, we have developed such imaging ligands via phage display libraries derived from llamas immunized with α-synuclein and tau preparations, respectively. These probes allow noninvasive and specific in vivo imaging of α-synuclein versus tau pathology in mice, with the brain signal correlating strongly with lesion burden. These small antibody derivatives have great potential for in vivo diagnosis of these diseases.

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Section: Discussionmentioning

confidence: 99%

Single-domain antibody–based noninvasive in vivo imaging of α-synuclein or tau pathology

et al. 2023

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“…Together, these results suggest that the binding of pT181-tau antibodies to the target antigen is disrupted to different extents by neighboring phosphorylation events in the context of the full-length protein. A goal for future studies will be to confirm these findings using a more quantitative method to measure the antibody affinities for full-length pT181-tau (e.g., BLI or ELISA). , …”

Section: Resultsmentioning

confidence: 99%

“…Moreover, we showed that our assay could yield valuable insights into the ability of a phosphomimetic mutation at a particular site in tau to mimic the effects of phosphorylation at the same site on antibody binding. In addition to being a validation tool for tau antibody specificity, our BLI assay could potentially be used to measure the levels of p-tau variants in biological samples when run in an alternative format involving the immobilization of biotin-conjugated p-tau antibodies to streptavidin biosensors …”

Section: Resultsmentioning

confidence: 99%

“…In addition to being a validation tool for tau antibody specificity, our BLI assay could potentially be used to measure the levels of p-tau variants in biological samples when run in an alternative format involving the immobilization of biotinconjugated p-tau antibodies to streptavidin biosensors. 31 By providing information about antibody binding kinetics, our BLI assay is ideally suited to addressing challenges associated with antibody cross-reactivity. Using our assay, we found that AT270 has significantly higher k on and k off values for the binding of pT175-versus pT181-tau peptide.…”

Section: Effects Of Neighboring Phosphorylation Events On Pt181-tau A...mentioning

confidence: 99%

“…A goal for future studies will be to confirm these findings using a more quantitative method to measure the antibody affinities for fulllength pT181-tau (e.g., BLI or ELISA). 31,32 Implications�BLI Assay as a Tool to Validate the Affinity and Specificity of pT181-Tau Antibodies. Our BLI assay offers several advantages over other antibody-based detection methods.…”

Section: Effects Of Neighboring Phosphorylation Events On Pt181-tau A...mentioning

confidence: 99%

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Effects of Neighboring Phosphorylation Events on the Affinities of pT181-Tau Antibodies

Min,

Mohallem,

Aryal

et al. 2023

Anal. Chem.

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Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies

Gaikwad,

Senapati,

Haque

et al. 2023

Alzheimer's & Dementia

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Aging, tau pathology, and chronic inflammation in the brain play crucial roles in synaptic loss, neurodegeneration, and cognitive decline in tauopathies, including Alzheimer's disease. Senescent cells accumulate in the aging brain, accelerate the aging process, and promote tauopathy progression through their abnormal inflammatory secretome known as the senescence‐associated secretory phenotype (SASP). Tau oligomers (TauO)—the most neurotoxic tau species—are known to induce senescence and the SASP, which subsequently promote neuropathology, inflammation, oxidative stress, synaptic dysfunction, neuronal death, and cognitive dysfunction. TauO, brain inflammation, and senescence are associated with heterogeneity in tauopathy progression and cognitive decline. However, the underlying mechanisms driving the disease heterogeneity remain largely unknown, impeding the development of therapies for tauopathies. Based on clinical and preclinical evidence, this review highlights the critical role of TauO and senescence in neurodegeneration. We discuss key knowledge gaps and potential strategies for targeting senescence and TauO to treat tauopathies.Highlights Senescence, oligomeric Tau (TauO), and brain inflammation accelerate the aging process and promote the progression of tauopathies, including Alzheimer's disease. We discuss their role in contributing to heterogeneity in tauopathy and cognitive decline. We highlight strategies to target senescence and TauO to treat tauopathies while addressing key knowledge gaps.

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Single domain antibodies targeting pathological tau protein: Influence of four IgG subclasses on efficacy and toxicity

Cited by 18 publications

References 82 publications

Single-domain antibody–based noninvasive in vivo imaging of α-synuclein or tau pathology

Single-domain antibody–based noninvasive in vivo imaging of α-synuclein or tau pathology

Effects of Neighboring Phosphorylation Events on the Affinities of pT181-Tau Antibodies

Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies

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