Anti-ApoE antibody given after plaque onset decreases Aβ accumulation and improves brain function in a mouse model of Aβ amyloidosis.
Apolipoprotein E (apoE) is the strongest known genetic risk factor for late onset Alzheimer's disease (AD). It influences amyloid-β (Aβ) 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 Aβ plaque load when given to APPswe/PS1ΔE9 (APP/PS1) mice starting before the onset of plaque deposition. To determine whether the anti-apoE antibody HJ6.3 affects Aβ 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 Aβ 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 Aβ pathology.
Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center.
Fan
F
Liao
MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129.
Yukiko
Y
Hori
MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129.
Eloise
E
Hudry
Department of Radiology, and.
Adam Q
AQ
Bauer
Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center.
Hong
H
Jiang
Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center.
Thomas E
TE
Mahan
Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center.
Katheryn B
KB
Lefton
Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center.
Tony J
TJ
Zhang
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110.
Joshua T
JT
Dearborn
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, and.
Jungsu
J
Kim
Department of Radiology, and.
Joseph P
JP
Culver
Harvard School of Public Health, Boston, Massachusetts 02115.
Rebecca
R
Betensky
Hope Center for Neurological Disorders, Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, Missouri 63110.
David F
DF
Wozniak
MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129.
Bradley T
BT
Hyman
Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, holtzman@neuro.wustl.edu.
David M
DM
Holtzman
D000544:Alzheimer Disease / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000686:Amyloidosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000276:immunology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D006470:Hemorrhage / Q000188:drug therapy / Q000209:etiology; D007794:Lameness, Animal / Q000188:drug therapy / Q000209:etiology; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D001057:Apolipoproteins E; C508853:PSEN1 protein, human; D053764:Presenilin-1; D002784:Cholesterol
Alzheimer's; amyloid; antibody; apolipoprotein E