title: Intracerebroventricular amyloid-beta antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice.
abstract: 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.
authors.affiliation: Medtronic, Inc., Minneapolis, MN 55432, USA.
authors.forename: Deepak R
authors.initials: DR
authors.lastname: Thakker
authors.forename: Marcy R
authors.initials: MR
authors.lastname: Weatherspoon
authors.forename: Jonathan
authors.initials: J
authors.lastname: Harrison
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Keene
authors.forename: Deanna S
authors.initials: DS
authors.lastname: Lane
authors.forename: William F
authors.initials: WF
authors.lastname: Kaemmerer
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Stewart
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Shafer
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D016657:Cerebral Amyloid Angiopathy / Q000150:complications / Q000517:prevention & control* / Q000628:therapy; D002543:Cerebral Hemorrhage / Q000209:etiology* / Q000517:prevention & control; D005239:Fear / Q000187:drug effects; D007114:Immunization / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies