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Monoclonal GW‐23B7 removes Aβ‐pathologic oligomers and produces cognitive rescue without toxicity in old TGSWDI AD model mice with advanced pathology
Author(s) -
Goni Fernando,
Pires Geoffrey,
Genovese Thomas S.,
Wisniewski Thomas
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.041235
Subject(s) - pathology , immunohistochemistry , cerebral amyloid angiopathy , medicine , parenchyma , toxicity , saline , cognitive decline , immunology , disease , dementia
Background We have previously demonstrated that a monoclonal antibody (GW‐23B7) which targets specific β‐sheet secondary structure present in all AD pathologic oligomers produces significant cognitive rescue linked to lowering of both Aβ and Tau oligomers in APP/PS1 and 3xTg mouse models. We have now tested the efficacy and safety of GW‐23B7 in a cerebral amyloid angiopathy (CAA) TgSwDI model. Method Two groups of 15 months old TgSwDI AD animals were used for the preclinical trial. One group was inoculated i.p. weekly for two months with 100 µg/animal of GW‐23B7 in sterile saline (IgM) or sterile saline vehicle alone. The animals then underwent locomotor and cognitive testing followed by the brains being harvested for immunohistochemical and biochemical analysis. Result The intact GW‐23B7 (IgM) interacted with the brain vasculature and penetrated the BBB in the treated group without inducing microhemorrhages as determined by Prussian Blue staining. Moreover, the treated group showed significant cognitive rescue compared to controls on the Barnes Maze, which correlated with a significant decrease of soluble aggregated Aβ in specific ELISA tests, and a significant decrease of vascular and parenchymal Aβ pathology, with a reduction of activated glia shown by ABl1, GFAP and CD‐45 immunohistochemistry. Conclusion We have shown that peripherally infused GW‐23B7‐IgM that only targets Aβ pathologic oligomers, reduces soluble oligomeric and deposited vascular and parenchymal pathology by an Aβ‐sequence independent mechanism avoiding ADCC induced microhemorrhages or inflammation. Our preclinical data testing GW‐23B7‐IgM in multiple AD models suggests that it could be safely translated to human AD clinical trials with a minimal possibility of ARIA or autoimmune toxicity complications.