Intracerebroventricular passive immunization with anti-oligoAbeta antibody in TgCRND8.
Based on the central dogma of beta-amyloid (Abeta) as a key seeding event in the pathogenesis of Alzheimer disease (AD), immunoneutralization strategies have been actively pursued both in AD and in models of AD as a potential means for treating AD. Both active and passive immunizations targeted at fibrillar Abeta successfully remove cerebral plaque load and attenuate Abeta-induced toxicity. Consistently with this, intracerebroventricular (ICV) passive immunization established in our laboratory using antibody against fibrillar Abeta (anti-fAbeta) reduced cerebral plaque load and reversed early synaptic deficits at pre/early plaque stage when there is an abundance of soluble dimeric/oligomeric Abeta but sparse fibrillar Abeta, indicating that anti-fAbeta-mediated partial neutralization of toxic oligomeric Abeta species might have reduced early synaptotoxicity. In the previous investigation, we found that immunoneutralization with anti-fAbeta transiently reduced cerebral Abeta and associated toxicity. The current investigation tested whether ICV im munization using antibody to conformationally changed oligomeric Abeta (anti-oligoAbeta) will overcome the transient restorative nature of anti-fAbeta and produce persistent, long-lasting preventive effects. Because oligomeric Abeta is strongly correlated with synaptotoxicity, we investigated whether immunoneutralization of oligomeric Abeta will reverse synaptic deficits by analyzing presynaptic molecular marker (SNAP-25) profile within hippocampal dendritic fields, where SNAP-25 is abundantly expressed. Results show that, in contrast to ICV anti-fAbeta antibody, ICV anti-oligoAbeta antibody significantly prevented cerebral Abeta build and almost completely restored SNAP-25 immunoreaction up to 8 weeks postinjection in TgCRND8 brain. Results show that ICV passive immunization with anti-oligoAbeta antibody might be an improved ICV immunization strategy for preventing permanent structural damage in AD.
Chauhan
Neelima B
NB
Research and Development (151), Jesse Brown VA Medical Center Chicago, Chicago, Illinois 60612, USA. nchauhan@uic.edu
D000544:Alzheimer Disease / Q000517:prevention & control*; D023582:Alzheimer Vaccines / Q000493:pharmacokinetics; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D004797:Enzyme-Linked Immunosorbent Assay; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism
D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D000906:Antibodies; D050825:Synaptosomal-Associated Protein 25