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Anti‐PrPC antibody rescues cognition and synapses in transgenic alzheimer mice
Abstract
Objective: Amyloid‐beta oligomers (Aßo) trigger the development of Alzheimer's disease (AD) pathophysiology. Cellular prion protein (Pr PC) initiates synaptic damage as a high affinity receptor for Aßo. Here, we evaluated the preclinical therapeutic efficacy of a fully human monoclonal antibody against Pr PC. This AZ 59 antibody selectively targets the Aβo binding site in the amino‐terminal unstructured domain of Pr PC to avoid any potential risk of direct toxicity. Methods: Potency of AZ 59 was evaluated by binding to Pr PC, blockade of Aβo interaction and interruption of Aβo signaling. AZ 59 was administered to mice by weekly intraperitoneal dosing and brain antibody measured. APP/PS 1 transgenic mice were treated with AZ 59 and assessed by memory tests, by brain biochemistry and by histochemistry for Aß, gliosis and synaptic density. Results: AZ 59 binds Pr PC with 100 pmol/L affinity and blocks human brain Aßo binding to Pr PC, as well as prevents synaptotoxic signaling. Weekly i.p. dosing of 20 mg/kg AZ 59 in a murine form achieves trough brain antibody levels greater than 10 nmol/L. Aged symptomatic APP/PS 1 transgenic mice treated with AZ 59 for 5–7 weeks show a full rescue of behavioral and synaptic loss phenotypes. This recovery occurs without clearance of plaque pathology or elimination of gliosis. AZ 59 treatment also normalizes synaptic signaling abnormalities in transgenic brain. These benefits are dose‐dependent and persist for at least 1 month after the last dose. Interpretation: Preclinical data demonstrate that systemic AZ 59 therapy rescues central synapses and memory function from transgenic Alzheimer's disease pathology, supporting a disease‐modifying therapeutic potential.
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Modulating TMEM97 with CT1812 and modulating PrPc rescue cognition in plaque-bearing transgenic mice.
“both modulating TMEM97 with CT1812 and modulating PrPc rescue cognition in plaque-bearing transgenic mice [15, 27]”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [15]
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“In brief, anti-PrP antibodies were isolated from an M13-based human singlechain variable fragments (scFv)-phage display library(32) using an alternating series of selections against biotinylated human and cynomolgus PrP(23-111).”
BackgroundMethodInfluentialCellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers
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Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease
Colom-Cadena, M., Toombs, J., Simzer, E., Holt, K., McGeachan, R., Tulloch, J., Jackson, R. J., Catterson, J. H., Spires-Jones, M. P., Rose, J., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-023-02679-6 · Cited by 44
Metadata
- Authors
- Cox, T. O., Gunther, E. C., Brody, A. H., Chiasseu, M. T., Stoner, A., Smith, L. M., Haas, L. T., Hammersley, J., Rees, G., Dosanjh, B., Groves, M., Gardener, M., Dobson, C., Vaughan, T., Chessell, I., Billinton, A., & Strittmatter, S. M.
- Affiliations
- Cellular Neuroscience Neurodegeneration & Repair Departments of Neurology and of Neuroscience Yale University School of Medicine New Haven 06536 Connecticut
- Antibody Discovery and Protein Engineering MedImmune Granta Park Cambridge CB21 6GH UK
- Neuroscience IMED Biotech Unit AstraZeneca Granta Park Cambridge CB21 6GH UK
- Venue
- Annals of Clinical and Translational Neurology
- Publisher
- Wiley
- Published
- 2019-02-27
- Volume
- 6
- Issue
- 3
- Pages
- 554-574
- ISSN
- 2328-9503
- PMC
- PMC6414488
- Cited by
- 33
- References
- 9
- Language
- en
- Funders
- National Institutes of Health (P50AG047270, R01AG034924, R35NS097283, RF1AG053000)
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