title: Simvastatin enhances immune responses to Aβ vaccination and attenuates vaccination-induced behavioral alterations.
abstract: Statins are widely used to lower cholesterol levels by inhibiting cholesterol biosynthesis. Some evidence has indicated that statins might have therapeutic and preventive benefits for Alzheimer's disease (AD). We and others also have shown the beneficial effect of statin treatment in reversing learning and memory deficits in animal models of AD. However, data from clinical trials are inconclusive. We previously documented that the adenovirus vector encoding 11 tandem repeats of Aβ1-6 fused to the receptor-binding domain (Ia) of Pseudomonas exotoxin A, AdPEDI-(Aβ1-6)(11), is effective in inducing an immune response against amyloid-β protein (Aβ) and reducing brain Aβ load in Alzheimer's mouse models. In the present study, we examined whether the administration of simvastatin can modulate immune and behavioral responses of C57BL/6 mice to vaccination. Simvastatin was given to the animals as a diet admixture for four weeks, followed by nasal vaccination with AdPEDI-(Aβ1-6)(11) once per week for four weeks. The cholesterol-lowering action of simvastatin was monitored by measuring the cholesterol levels in plasma. Simvastatin significantly increased the number of the mice responding to vaccination compared with the mice receiving only AdPEDI-(Aβ1-6)(11). Immunoglobulin isotyping revealed that the vaccination predominantly induced Th2 immune responses. Simvastatin treatment prevented Aβ-induced production of IFN-γ in splenocytes. The adenovirus vaccination altered mouse behavior in T- and elevated plus-maze tests and simvastatin counteracted such behavioral changes. Our results indicate that simvastatin clearly enhances the immune responses of C57BL/6 mice to the nasal vaccination with AdPEDI-(Aβ1-6)(11). Simvastatin may be effective in preventing behavioral changes associated with vaccination.
authors.affiliation: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, PO Box 1649, Peoria, IL 61656, USA.
authors.forename: Jinghong
authors.initials: J
authors.lastname: Kou
authors.forename: Hong-Duck
authors.initials: HD
authors.lastname: Kim
authors.forename: Jingji
authors.initials: J
authors.lastname: Jin
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Cao
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Robert
authors.initials: R
authors.lastname: Lalonde
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Fukuchi
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000280:Administration, Inhalation; D023582:Alzheimer Vaccines / Q000008:administration & dosage* / Q000276:immunology / Q000627:therapeutic use; D016229:Amyloid beta-Peptides / Q000008:administration & dosage* / Q000276:immunology; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D000924:Anticholesteremic Agents; D007371:Interferon-gamma; D019821:Simvastatin