Immunization with either prion protein fragment 95-123 or the fragment-specific antibodies rescue memory loss and neurodegenerative phenotype of neurons in olfactory bulbectomized mice

Epidemiological studies demonstrated association between head injury (I-II) and the subsequent development of Alzheimer's disease (AD). Certain hallmarks of AD, e.g. amyloid-beta (A beta) containing deposits, may be found in patients following traumatic BI (TBI). Recent studies uncover the cellular prion protein, PrPC, as a receptor for soluble polymeric forms of A beta (sA beta) which are an intermediate of such deposits. We aimed to test the hypothesis that targeting of PrPC can prevent A beta related spatial memory deficits in olfactory bulbectomized (OBX) mice utilized here to resemble some clinical features of AD, such as increased level of A beta, memory loss and deficit of the CNS cholin- and serotonin-ergic systems. We demonstrated that immunization with the a.a. 95-123 fragment of cellular prion (PrP-I) recovered cortical and hippocampus neurons from OBX induced degeneration, rescued spatial memory loss in Morris water maze test and significantly decrease the A beta level in brain tissue of these animals. Affinity purified anti-PrP-I antibodies rescued pre-synaptic biomarker synaptophysin eliciting similar effect on memory of OBX mice, and protected hippocampal neurones from A beta(25-35)-induced toxicity in vitro. Immunization OBX mice with a.a. 200-213 fragment of cellular prion (PrP-II) did not reach a significance in memory protection albeit having similar to PrP-I immunization impact on A beta level in brain tissue. The observed positive effect of targeting the PrP-I by either active or passive immunization on memory of OBX mice revealed the involvement of the PrPC in AD-like pathology induced by olfactory bulbectomy. This OBX model may be a useful tool for mechanistic and preclinical therapeutic investigations into the association between PrPC and AD. (C) 2013 Elsevier Inc. All rights reserved.