Based on the central dogma of β-amyloid (Aβ) 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 Aβ successfully remove cerebral plaque load and attenuate Aβ-induced toxicity. Consistently with this, intracerebroventricular (ICV) passive immunization established in our laboratory using antibody against fibrillar Aβ (anti-fAβ) reduced cerebral plaque load and reversed early synaptic deficits at pre/early plaque stage when there is an abundance of soluble dimeric/oligomeric Aβ but sparse fibrillar Aβ, indicating that anti-fAβ-mediated partial neutralization of toxic oligomeric Aβ species might have reduced early synaptotoxicity. In the previous investigation, we found that immunoneutralization with anti-fAβ transiently reduced cerebral Aβ and associated toxicity. The current investigation tested whether ICV im munization using antibody to conformationally changed oligomeric Aβ (anti-oligoAβ) will overcome the transient restorative nature of anti-fAβ and produce persistent, long-lasting preventive effects. Because oligomeric Aβ is strongly correlated with synaptotoxicity, we investigated whether immunoneutralization of oligomeric Aβ 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-fAβ antibody, ICV anti-oligoAβ antibody significantly prevented cerebral Aβ build and almost completely restored SNAP-25 immunoreaction up to 8 weeks postinjection in TgCRND8 brain. Results show that ICV passive immunization with anti-oligoAβ antibody might be an improved ICV immunization strategy for preventing permanent structural damage in AD. © 2006 Wiley-Liss, Inc.