IgM response against amyloid-beta in aging: a potential peripheral protective mechanism

Background: The immune system plays a major role in the pathogenesis of age-related dementia, including Alzheimer's disease (AD). An insight into age-associated changes in the immune response to amyloid-beta (A beta) in individuals without AD may be beneficial in identifying mechanisms preventing accumulation of A beta. Methods: We examined the response of human monocyte-derived dendritic cells (DCs), T cells, and peripheral blood mononuclear cells (PBMCs) from healthy aged and young subjects to A beta peptide 1-42, A beta fibrils, and recombinant, nonaggregated tau-4 protein with a view to understand the role of peripheral immunity in AD. Results: Our studies revealed that DCs from healthy aged subjects display weak reactivity towards the A beta peptide and no reactivity towards A beta fibrils and tau compared with their young counterparts. An analysis of old and young PBMCs revealed that there is no significant T-cell memory against A beta peptide, fibrils, or tau. Remarkably, the plasma levels of IgM antibodies specific to A beta peptide 1-42 were significantly increased in aged subjects compared with young subjects, while IgG levels were comparable. A beta peptide-specific IgM and IgG levels were also determined in the plasma of AD subjects compared with age-matched controls to demonstrate that the immune response against A beta is stronger in AD patients. A decline in A beta peptide-specific IgM antibodies was observed in AD patients compared with age-matched controls. In contrast, the levels of IgG as well as interleukin-21, the major cytokine involved in class switching, were increased in AD and patients with mild cognitive impairment, indicating a strong immune response against A beta. Conclusions: Collectively, low immunogenicity of A beta in healthy controls may prevent inflammation while the generation of specific IgM antibodies may help in the clearance of A beta in healthy subjects.