P2‐063: SOLUBLE Aβ‐OLIGOMER–SELECTIVE ANTIBODY ACU‐3B3 REDUCES AMYLOID PATHOLOGY AND IMPROVES MULTIPLE BEHAVIORAL DOMAINS IN A MOUSE MODEL OF ALZHEIMER'S DISEASE
Year: 2019
Type: article
Abstract: Considerable evidence suggests that amyloid-beta (Aβ) contributes to Alzheimer's disease (AD) pathogenesis. Despite initial failures, some clinical trials targeting Aβ by immunotherapy showed reduced Aβ pathology and moderate beneficial effects on cognitive functions. Because Aβ exists in multiple assembly states, we tested the in vivo efficacy of the Aβ-oligomer selective antibody ACU-3B3, the murine precursor to the clinical candidate antibody ACU-193, which has a different anti-Aβ profile than previously developed antibodies targeting monomeric or fibrillar Aβ. hAPPJ20 mice received weekly intraperitoneal treatments with vehicle or ACU-3B3 at 5, 10, or 20 mg/kg. Treatment began at the earliest stages of amyloid deposition (3–5 months) and continued for 10 weeks until mice were 5–7 months old. During the treatment period, mice were assessed for locomotor activity, emotional behaviors, and cognitive functions. Across all experimental groups, mouse body weights remained stable during the 10-week period, indicating that ACU-3B3 was well tolerated. ACU-3B3 treatment reduced the hyperactivity phenotype of hAPPJ20 mice in the open field test and the Y-maze. Emotional alterations of hAPPJ20 mice in the elevated plus-maze were also normalized. Cognitive performance was assessed in the context-dependent habituation test and the Morris water maze. ACU-3B3 treatment enhanced cognitive performance in the novel environment habituation test (context learning) and during the visible platform water maze training (non-spatial learning), but not in the hidden version of the test (spatial learning). After treatment, brains were collected for pathological analyses. ACU-3B3 treatment reduced amyloid deposits in the hippocampus and cortex in a dose-dependent manner. In postmortem human brain from AD patients and hAPPJ20 mice, ACU-3B3 labelled neocortical diffuse and neuritic amyloid plaques with a distribution pattern and density similar but not identical, to those observed in adjacent sections stained with Aβ antibodies 6E10 and 82E1. Our data indicate that ACU-3B3 targets an Aβ assembly state that is on path for in vivo amyloid formation and underlying behavioral deficits in hAPPJ20 mice, and clinical benefits may improve with second generation passive immunization approaches targeting soluble Ab oligomers. Sponsored by Acumen Pharmaceuticals Inc.
Source: Alzheimer s & Dementia
Authors: Keran Ma, Maria M. Martinez-Losa, YueQiang Xue, Abdullah Khan, Kaitlyn Ho, Jean-Cosme Dodart, Jasna Jerecic, Inma Cobos, Jorge J. Palop
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2980826502