RESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder that impairs memory and cognition. Targeting amyloid-ß (Aß) may be currently the most promising immunotherapeutic strategy for AD. In this study, a recombinant chimeric 6Aß15-THc-C immunogen was formulated with alum adjuvant as a novel Aß B-cell epitope candidate vaccine (rCV02) for AD. We examined its efficacy in preventing the cognitive deficit and synaptic impairment in 3 × Tg-AD mice. Using a toxin-derived carrier protein, the rCV02 vaccine elicited robust Aß-specific antibodies that markedly reduced AD-like pathology and improved behavioral performance in 3 × Tg-AD mice. Along with the behavioral improvement in aged 3 × Tg-AD mice, rCV02 significantly decreased calpain activation concurrent with reduced soluble Aß or oligomeric forms of Aß, probably by preventing dynamin 1 and PSD-95 degradation. Our data support the hypothesis that reducing Aß levels in rCV02-immunized AD mice increases the levels of presynaptic dynamin 1 and postsynaptic PSD-95 allowing functional recovery of cognition. In conclusion, this novel and highly immunogenic rCV02 shows promise as a new candidate prophylactic vaccine for AD and may be useful for generating rapid and strong Aß-specific antibodies in AD patients with pre-existing memory Th cells generated after immunization with conventional tetanus toxoid vaccine.
Asunto(s)
Enfermedad de Alzheimer/terapia , Vacunas contra el Alzheimer/administración & dosificación , Péptidos beta-Amiloides/efectos de los fármacos , Cognición/efectos de los fármacos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Vacunas contra el Alzheimer/farmacología , Animales , Calpaína/metabolismo , Modelos Animales de Enfermedad , Homólogo 4 de la Proteína Discs Large/metabolismo , Dinamina I/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Ratones , Ratones Transgénicos , Vacunas SintéticasRESUMEN
Sepsis, which refers to a systemic inflammatory response syndrome resulting from a microbial infection, represents the leading cause of death in intensive care units. The pathogenesis of sepsis remains poorly understood although it is attributable to dysregulated immune responses orchestrated by innate immune cells that are sequentially released early (e.g., tumor necrosis factor(TNF), interleukin-1(IL-1), and interferon-γ(IFN-γ)) and late (e.g., high mobility group box 1(HMGB1)) pro-inflammatory mediators. As a ubiquitous nuclear protein, HMGB1 can be passively released from pathologically damaged cells, thereby converging infection and injury on commonly dysregulated inflammatory responses. We review evidence that supports extracellular HMGB1 as a late mediator of inflammatory diseases and discuss the potential of several Chinese herbal components as HMGB1-targeting therapies. We propose that it is important to develop strategies for specifically attenuating injury-elicited inflammatory responses without compromising the infection-mediated innate immunity for the clinical management of sepsis and other inflammatory diseases.