Vaccination induced changes in pro-inflammatory cytokine levels as an early putative biomarker for cognitive improvement in a transgenic mouse model for Alzheimer disease

摘要

Several pieces of experimental evidence suggest that administration of anti-beta amyloid (A beta) vaccines, passive anti-A beta antibodies or anti-inflammatory drugs can reduce A beta deposition as well as associated cognitive/behavioral deficits in an Alzheimer disease (AD) transgenic (Tg) mouse model and, as such, may have some efficacy in human AD patients as well. In the investigation reported here an A beta 1-42 peptide vaccine was administered to 16-month old APP+PS1 transgenic (Tg) mice in which A beta deposition, cognitive memory deficits as well as levels of several pro-inflammatory cytokines were measured in response to the vaccination regimen. After vaccination, the anti-A beta 1-42 antibody-producing mice demonstrated a significant reduction in the sera levels of 4 pro-inflammatory cytokines (TNF-alpha, IL-6, IL-1 alpha, and IL-12). Importantly, reductions in the cytokine levels of TNF-alpha and IL-6 were correlated with cognitive/behavioral improvement in the Tg mice. However, no differences in cerebral A beta deposition in these mice were noted among the different control and experimental groups, i.e., A beta 1-42 peptide vaccinated, control peptide vaccinated, or non-vaccinated mice. However, decreased levels of pro-inflammatory cytokines as well as improved cognitive performance were noted in mice vaccinated with the control peptide as well as those immunized with the A beta 1-42 peptide. These findings suggest that reduction in pro-inflammatory cytokine levels in these mice may be utilized as an early biomarker for vaccination/ treatment induced amelioration of cognitive deficits and are independent of A beta deposition and, interestingly, antigen specific A beta 1-42 vaccination. Since cytokine changes are typically related to T cell activation, the results imply that T cell regulation may have an important role in vaccination or other immunotherapeutic strategies in an AD mouse model and potentially in AD patients. Overall, these cytokine changes may serve as a predictive marker for AD development and progression as well as having potential therapeutic implications.