Anti-ApoE Antibody Given after Plaque Onset Decreases A beta Accumulation and Improves Brain Function in a Mouse Model of A beta Amyloidosis

作者:Liao Fan; Hori Yukiko; Hudry Eloise; Bauer Adam Q; Jiang Hong; Mahan Thomas E; Lefton Katheryn B; Zhang Tony J; Dearborn Joshua T; Kim Jungsu; Culver Joseph P; Betensky Rebecca; Wozniak David F; Hyman Bradley T; Holtzman David M*
来源:Journal of Neuroscience, 2014, 34(21): 7281-7292.
DOI:10.1523/JNEUROSCI.0646-14.2014

摘要

Apolipoprotein E (apoE) is the strongest known genetic risk factor for late onset Alzheimer's disease (AD). It influences amyloid-beta(A beta) clearance and aggregation, which likely contributes in large part to its role in AD pathogenesis. We recently found that HJ6.3, a monoclonal antibody against apoE, significantly reduced A beta plaque load when given to APPswe/PS1 Delta E9 (APP/PS1) mice starting before the onset of plaque deposition. To determine whether the anti-apoE antibody HJ6.3 affects A beta plaques, neuronal network function, and behavior in APP/PS1 mice after plaque onset, we administered HJ6.3 (10 mg/kg/week) or PBS intraperitoneally to 7-month-old APP/PS1 mice for 21 weeks. HJ6.3 mildly improved spatial learning performance in the water maze, restored resting-state functional connectivity, and modestly reduced brain A beta plaque load. There was no effect of HJ6.3 on total plasma cholesterol or cerebral amyloid angiopathy. To investigate the underlying mechanisms of anti-apoE immunotherapy, HJ6.3 was applied to the brain cortical surface and amyloid deposition was followed over 2 weeks using in vivo imaging. Acute exposure to HJ6.3 affected the course of amyloid deposition in that it prevented the formation of new amyloid deposits, limited their growth, and was associated with occasional clearance of plaques, a process likely associated with direct binding to amyloid aggregates. Topical application of HJ6.3 for only 14 d also decreased the density of amyloid plaques assessed postmortem. Collectively, these studies suggest that anti-apoE antibodies have therapeutic potential when given before or after the onset of A beta pathology.

  • 出版日期2014-5-21