Immunotherapy reduces vascular amyloid-beta in PDAPP mice.
In addition to parenchymal amyloid-beta (Abeta) plaques, Alzheimer's disease (AD) is characterized by Abeta in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in the majority of patients. Recent studies investigating vascular Abeta (VAbeta) in amyloid precursor protein transgenic mice have suggested that passive immunization with anti-Abeta antibodies may clear parenchymal amyloid but increase VAbeta and the incidence of microhemorrhage. However, the influences of antibody specificity and exposure levels on VAbeta and microhemorrhage rates have not been well established, nor has any clear causal relationship been identified. This report examines the effects of chronic, passive immunization on VAbeta and microhemorrhage in PDAPP mice by comparing antibodies with different Abeta epitopes (3D6, Abeta(1-5); 266, Abeta(16-23)) and performing a 3D6 dose-response study. VAbeta and microhemorrhage were assessed using concomitant Abeta immunohistochemistry and hemosiderin detection. 3D6 prevented or cleared VAbeta in a dose-dependent manner, whereas 266 was without effect. Essentially complete absence of VAbeta was observed at the highest 3D6 dose, whereas altered morphology suggestive of ongoing clearance was seen at lower doses. The incidence of microhemorrhage was increased in the high-dose 3D6 group and limited to focal, perivascular sites. These colocalized with Abeta deposits having altered morphology and apparent clearance in the lower-dose 3D6 group. Our results suggest that passive immunization can reduce VAbeta levels, and modulating antibody dose can significantly mitigate the incidence of microhemorrhage while still preventing or reducing VAbeta. These observations raise the possibility that Abeta immunotherapy can potentially slow or halt the course of CAA development in AD that is implicated in vascular dysfunction.
Schroeter
Sally
S
Elan Pharmaceuticals, South San Francisco, California 94080, and Wyeth Pharmaceuticals, Cambridge, Massachusetts 02140, USA.
Khan
Karen
K
Barbour
Robin
R
Doan
Minhtam
M
Chen
Ming
M
Guido
Terry
T
Gill
Davinder
D
Basi
Guriqbal
G
Schenk
Dale
D
Seubert
Peter
P
Games
Dora
D
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D016657:Cerebral Amyloid Angiopathy / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D002536:Cerebral Arteries / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D005260:Female; D007116:Immunization, Passive / Q000379:methods*; D008657:Metabolic Clearance Rate / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D016896:Treatment Outcome
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D000939:Epitopes