RT Journal Article
SR Electronic
T1 Immunotherapy Reduces Vascular Amyloid-β in PDAPP Mice
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 6787
OP 6793
DO 10.1523/JNEUROSCI.2377-07.2008
VO 28
IS 27
A1 Schroeter, Sally
A1 Khan, Karen
A1 Barbour, Robin
A1 Doan, MinhTam
A1 Chen, Ming
A1 Guido, Terry
A1 Gill, Davinder
A1 Basi, Guriqbal
A1 Schenk, Dale
A1 Seubert, Peter
A1 Games, Dora
YR 2008
UL http://www.jneurosci.org/content/28/27/6787.abstract
AB In addition to parenchymal amyloid-β (Aβ) plaques, Alzheimer's disease (AD) is characterized by Aβ in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in the majority of patients. Recent studies investigating vascular Aβ (VAβ) in amyloid precursor protein transgenic mice have suggested that passive immunization with anti-Aβ antibodies may clear parenchymal amyloid but increase VAβ and the incidence of microhemorrhage. However, the influences of antibody specificity and exposure levels on VAβ 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 VAβ and microhemorrhage in PDAPP mice by comparing antibodies with different Aβ epitopes (3D6, Aβ1–5; 266, Aβ16–23) and performing a 3D6 dose–response study. VAβ and microhemorrhage were assessed using concomitant Aβ immunohistochemistry and hemosiderin detection. 3D6 prevented or cleared VAβ in a dose-dependent manner, whereas 266 was without effect. Essentially complete absence of VAβ 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 Aβ deposits having altered morphology and apparent clearance in the lower-dose 3D6 group. Our results suggest that passive immunization can reduce VAβ levels, and modulating antibody dose can significantly mitigate the incidence of microhemorrhage while still preventing or reducing VAβ. These observations raise the possibility that Aβ immunotherapy can potentially slow or halt the course of CAA development in AD that is implicated in vascular dysfunction.