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Publication : Intracerebroventricular amyloid-beta antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice.

First Author  Thakker DR Year  2009
Journal  Proc Natl Acad Sci U S A Volume  106
Issue  11 Pages  4501-6
PubMed ID  19246392 Mgi Jnum  J:146774
Mgi Id  MGI:3838432 Doi  10.1073/pnas.0813404106
Citation  Thakker DR, et al. (2009) Intracerebroventricular amyloid-beta antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice. Proc Natl Acad Sci U S A 106(11):4501-6
abstractText  Although immunization against amyloid-beta (Abeta) holds promise as a disease-modifying therapy for Alzheimer disease (AD), it is associated with an undesirable accumulation of amyloid in the cerebrovasculature [i.e., cerebral amyloid angiopathy (CAA)] and a heightened risk of micro-hemorrhages. The central and peripheral mechanisms postulated to modulate amyloid with anti-Abeta immunotherapy remain largely elusive. Here, we compared the effects of prolonged intracerebroventricular (i.c.v.) versus systemic delivery of anti-Abeta antibodies on the behavioral and pathological changes in an aged Tg2576 mouse model of AD. Prolonged i.c.v. infusions of anti-Abeta antibodies dose-dependently reduced the parenchymal plaque burden, astrogliosis, and dystrophic neurites at doses 10- to 50-fold lower than used with systemic delivery of the same antibody. Both i.c.v. and systemic anti-Abeta antibodies reversed the behavioral impairment in contextual fear conditioning. More importantly, unlike systemically delivered anti-Abeta antibodies that aggravated vascular pathology, i.c.v.-infused antibodies globally reduced CAA and associated micro-hemorrhages. We present data suggesting that the divergent effects of i.c.v.-delivered anti-Abeta antibodies result from gradually engaging the local (i.e., central) mechanisms for amyloid clearance, distinct from the mechanisms engaged by high doses of anti-Abeta antibodies that circulate in the vasculature following systemic delivery. With robust efficacy in reversing AD-related pathology and an unexpected benefit in reducing CAA and associated micro-hemorrhages, i.c.v.-targeted passive immunotherapy offers a promising therapeutic approach for the long-term management of AD.
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