A conformation-specific antibody against oligomeric β-amyloid restores neuronal integrity in a mouse model of Alzheimer's disease
| العنوان: | A conformation-specific antibody against oligomeric β-amyloid restores neuronal integrity in a mouse model of Alzheimer's disease |
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| المؤلفون: | Michael R. Sierks, Ping He, Philip Schulz |
| المصدر: | The Journal of Biological Chemistry |
| بيانات النشر: | American Society for Biochemistry and Molecular Biology, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Protein Conformation, Biochemistry, Mice, Amyloid precursor protein, scFv, single chain antibody variable domain fragment, Neurons, biology, Chemistry, oligomeric beta amyloid, Neurogenesis, DCX, doublecortin, Brain, Editors' Pick, Alzheimer's disease, Cell biology, BBB, blood brain barrier, medicine.anatomical_structure, Disease Progression, SYP, synaptophysin, AD, Alzheimer's disease, Intracellular, Research Article, Genetically modified mouse, Aβ, amyloid β, rAAV, recombinant human adeno-associated virus, transgenic mice, Blood–brain barrier, Protein Aggregation, Pathological, 03 medical and health sciences, MAP2, microtubule-associated protein 2, Alzheimer Disease, APP, amyloid precursor protein, medicine, Animals, Humans, ApoB, apolipoprotein B, Molecular Biology, Neuroinflammation, Amyloid beta-Peptides, 030102 biochemistry & molecular biology, GFAP, glial fibrillary acidic protein, Cell Biology, medicine.disease, neuron, Disease Models, Animal, ND, nondementia, 030104 developmental biology, single-chain antibody, biology.protein, Neuron, Single-Chain Antibodies |
| الوصف: | Conformationally distinct aggregates of the amyloid β (Aβ) peptide accumulate in brains of patients with Alzheimer's disease (AD), but the roles of the different aggregates in disease progression are not clear. We previously isolated two single-chain variable domain antibody fragments (scFvs), C6T and A4, that selectively bind different toxic conformational variants of oligomeric Aβ. Here, we utilize these scFvs to localize the presence of these Aβ variants in human AD brain and to demonstrate their potential as therapeutic agents for treating AD. Both A4 and C6T label oligomeric Aβ in extracellular amyloid plaques, whereas C6T also labels intracellular oligomeric Aβ in human AD brain tissue and in an AD mouse model. For therapeutic studies, the A4 and C6T scFvs were expressed in the AD mice by viral infection of liver cells. The scFvs were administered at 2 months of age, and mice sacrificed at 9 months. The scFvs contained a peptide tag to facilitate transport across the blood brain barrier. While treatment with C6T only slightly decreased Aβ deposits and plaque-associated inflammation, it restored neuronal integrity to WT levels, significantly promoted growth of new neurons, and impressively rescued survival rates to WT levels. Treatment with A4 on the other hand significantly decreased Aβ deposits but did not significantly decrease neuroinflammation or promote neuronal integrity, neurogenesis, or survival rate. These results suggest that the specific Aβ conformation targeted in therapeutic applications greatly affects the outcome, and the location of the targeted Aβ variants may also play a critical factor. |
| اللغة: | English |
| تدمد: | 1083-351X 0021-9258 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::eb895cc10e4d58759d80fdf7e5d922ccTest http://europepmc.org/articles/PMC7948963Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....eb895cc10e4d58759d80fdf7e5d922cc |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1083351X 00219258 |
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