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 (HI) and the subsequent development of Alzheimer's disease (AD). Certain hallmarks of AD, e.g. amyloid-β (Aβ) containing deposits, may be found in patients following traumatic BI (TBI). Recent studies uncover the cellular prion protein, PrP(C), as a receptor for soluble polymeric forms of Aβ (sAβ) which are an intermediate of such deposits. We aimed to test the hypothesis that targeting of PrP(C) can prevent Aβ related spatial memory deficits in olfactory bulbectomized (OBX) mice utilized here to resemble some clinical features of AD, such as increased level of Aβ, 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 Aβ 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 Aβ25-35-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 Aβ 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 PrP(C) 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 PrP(C) and AD.
Institute of Cell Biophysics, Russian Academy of Sciences, ul. Institutskaya, 3. Pushchino, Russia. Electronic address: nbobkova@mail.ru.
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Bobkova
Institute of Cell Biophysics, Russian Academy of Sciences, ul. Institutskaya, 3. Pushchino, Russia. Electronic address: nmedvinskaya@rambler.ru.
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Medvinskaya
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya, 16/10, 117997 Moscow, Russia. Electronic address: aneskaminina@mail.ru.
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Kamynina
Institute of Cell Biophysics, Russian Academy of Sciences, ul. Institutskaya, 3. Pushchino, Russia. Electronic address: iualex@rambler.ru.
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Aleksandrova
Institute of Cell Biophysics, Russian Academy of Sciences, ul. Institutskaya, 3. Pushchino, Russia. Electronic address: nprivat@rambler.ru.
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Nesterova
Institute of Cell Biophysics, Russian Academy of Sciences, ul. Institutskaya, 3. Pushchino, Russia. Electronic address: sam.alexandre@gmail.com.
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Samokhin
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya, 16/10, 117997 Moscow, Russia. Electronic address: koroev@mx.ibch.ru.
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Koroev
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya, 16/10, 117997 Moscow, Russia. Electronic address: filatova07@mail.ru.
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Filatova
Institute of Cell Biophysics, Russian Academy of Sciences, ul. Institutskaya, 3. Pushchino, Russia. Electronic address: pgta01@mail.ru.
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Nekrasov
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, WC1N 3BG London, UK. Electronic address: a.abramov@ucl.ac.uk.
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Abramov
Institute of Cell Biophysics, Russian Academy of Sciences, ul. Institutskaya, 3. Pushchino, Russia; Department of Biology, Chemical Diversity Research Institute (CDRI), Rabochaya St., 2-A, 141400 Khimki, Moscow Region, Russia; BioBusiness Incubator, Moscow Institute of Physics and Technology, Institutsky pereulok, 9, Dolgoprudny, Moscow Region 141700, Russia. Electronic address: sergey.leonov@yahoo.com.
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Leonov
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya, 16/10, 117997 Moscow, Russia. Electronic address: volpina@ibch.ru.
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Volpina
D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000276:immunology; D006624:Hippocampus / Q000473:pathology; D007114:Immunization; D007116:Immunization, Passive; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000628:therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D009410:Nerve Degeneration / Q000628:therapy*; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000276:immunology*; D009830:Olfactory Bulb / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology*; D018621:PrPC Proteins / Q000276:immunology*; D011328:Prions / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013702:Temporal Lobe / Q000473:pathology
D016229:Amyloid beta-Peptides; D000906:Antibodies; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D018621:PrPC Proteins; D011328:Prions; C000591316:prion protein (95-123)
Amyloid; Antibody; Bulbectomy; Memory; Peptide; Prion