Microglial alterations in human Alzheimer's disease following Aβ42 immunization

Aims: In Alzheimer's disease (AD), microglial activation prompted by the presence of amyloid has been proposed as an important contributor to the neurodegenerative process. Conversely following A beta immunization, phagocytic microglia have been implicated in plaque removal, potentially a beneficial effect. We have investigated the effects of A beta 42 immunization on microglial activation and the relationship with A beta 42 load in human AD. Methods: Immunostaining against A beta 42 and microglia (CD68 and HLA-DR) was performed in nine immunized AD cases (iAD - AN1792, Elan Pharmaceuticals) and eight unimmunized AD (cAD) cases. Results: Although the A beta 42 load (% area stained of total area examined) was lower in the iAD than the cAD cases (P = 0.036), the CD68 load was higher (P = 0.046). In addition, in the iAD group, the CD68 level correlated with the A beta 42 load, consistent with the immunization upregulating microglial phagocytosis when plaques are present. However, in two long-surviving iAD patients in whom plaques had been extensively cleared, the CD68 load was less than in controls. HLA-DR quantification did not show significant difference implying that the microglial activation may have related specifically to their phagocytic function. CD68 and HLA-DR loads in the pons were similar in both groups, suggesting that the differences in microglial activation in the cortex were due to the presence of AD pathology. Conclusion: Our findings suggest that A beta 42 immunization modifies the function of microglia by increasing their phagocytic activity and when plaques have been cleared, the level of phagocytosis is decreased below that seen in unimmunized AD.