UC Irvine

Abstract Alzheimer’s disease (AD) has become the most common form of dementia in the elderly. Recent studies have highlighted the role of inflammation and the immune system in the etiology of AD. However, there is a key gap in knowledge regarding the immune processes in healthy aged individuals as compared to AD patients. We have recently demonstrated that healthy aged subjects display a weak immune/inflammatory response to Amyloid beta–Aβ peptide (1–42) characterized by high IgM antibody responses. In contrast, MCI or AD patients exhibit high levels of IgG antibody against Aβ indicative of a strong immune response. IL-21, an inflammatory cytokine that enhances the differentiation of B cells and facilitates the class switching of IgM to IgG antibodies, is also upregulated in the plasma of AD patients compared to healthy aged controls. In support of these human data, our pre-clinical in vivo experiments using the 5xFAD mouse model of AD also display increased immune activation as compared to age-matched control mice. Similar to humans, we observed a decreased IgM and increased IgG response against Aβ. Furthermore the increased IgM antibody response correlated negatively with cognitive dysfunction. In addition, we also observed an increase in the proportions of T follicular helper (Tfh) cells which secrete IL-21, and enhance the B cell class switch to IgG antibodies in AD mice. In summary, our data indicate that weak immune/inflammatory response against Aβ is protective and facilitates the clearance of Aβ without inducing damaging levels of inflammation. In contrast, strong immune/inflammatory response against Aβ such as those observed in MCI and AD subjects and mice enhance inflammation and aid AD progression.