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Job Title
POSTDOC
Academic Rank
Fellow or Postdoc
Department
Neurology
Authors
Praveen Bathini, PhD, Martine Grenon, Maria-Giusy Papavergi, Jens-Ulrich Rahfeld, Stephan Schilling, Stefan Tasler, and Cynthia A. Lemere
Principal Investigator
Cynthia Lemere
Categories
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Pyroglutamate-3Aβ (pGlu3-Aβ) is a toxic N-terminally truncated modified form of Aβ that causes faster aggregation and seeding of plaques, making it an essential target in Alzheimer’s disease (AD). Anti-amyloid monoclonal antibodies (mAbs), e.g., donanemab (anti-pGlu3Aβ) and bapineuzumab, are associated with Amyloid-Related Imaging Abnormalities (ARIA) involving vasogenic edema and microhemorrhages in AD patients, especially ApoE4 carriers. Previously, we demonstrated plaque reduction and cognitive stabilization using a murine anti-pGlu3Ab mAb, 07/2a. Here, we tested a novel CDC-mutant version of 07/2a (07/2a-k) engineered to avoid complement activation, clear Aβ and potentially reduce vascular-related inflammation caused by anti-amyloid antibodies in plaque-rich 16-month-old APP/PS1dE9;hApoE4 mice, an AD-like model. Mice were treated weekly (i.p.) for 15 weeks with 350μg 07/2a-k or 3D6-L (murine bapineuzumab precursor) mAbs. Both treatments reduced cerebral soluble pGlu3-Aβ(3-42) levels and hippocampal fibrillar plaques. 3D6-L treatment also reduced insoluble pGlu3-Aβ(3-42) and general Aβx-42 levels, but it induced microhemorrhages, increased C1q immunoreactivity in the cerebellar and meningeal vessels, and increased microglial-C1q colocalization near plaques, which was not seen in the 07/2a-k group. In conclusion, complement activation by anti-amyloid mAbs may play a role in amyloid clearance and ARIA. Further studies are required to pinpoint the mechanisms underlying ARIA to develop mitigation strategies.
Amyloid-beta protein (Aβ) is a sticky protein that accumulates in clumps outside nerve cells (“plaques”) and in blood vessel walls in the brains of patients with Alzheimer’s disease (AD). Scientists have developed anti-amyloid antibody treatments to bind and remove this protein, including some harmful versions (e.g., pyroglutamate3-Aβ, pGlu3-Aβ), that have shown cognitive benefit in people with early-stage AD. However, some of these antibodies cause side effects like brain swelling and microhemorrhages, especially in patients with an ApoE4 genotype which increases AD risk. We tested a modified anti-pGlu3-Aβ antibody, 07/2a-k, in an amyloid mouse model with human ApoE4. The antibody was altered to reduce inflammation caused by the treatment. Aged mice were given 15 weekly injections of the antibody or a general anti-amyloid antibody, 3D6-L. Both treatments reduced harmful pGlu3-Aβ levels and brain plaques. However, 3D6-L also caused more brain bleeding and increased inflammation. 07/2a-k induced less inflammation and brain bleeding, which may be due to its lack of immune stimulation or the low levels of its target, pGlu3-Aβ, in mouse blood vessels. AD patients have more vascular pGlu3-Aβ, and the humanized version of 07/2a-k is hoped to avoid the vascular side effects by inducing less inflammation.
