A current working hypothesis in the field of AD research is that preventing the accumulation of Aß peptides will slow or prevent cognitive decline. Two main strategies for accomplishing this goal have been pursued in recent years. The first strategy is to derive pharmaceuticals that will block the activity of the γ-secretase, which drives the generation of toxic amyloidogenic fragments from APP. This strategy is similar to that applied in the clinical use of statins, which inhibit HMG-CoA reductase, thus lowering cholesterol by preventing deposition and promoting clearance, and decreasing the incidence of disease in vulnerable populations. The second strategy is to directly target the clearance of Aß from the neuropil. Recent work has demonstrated that active immunization of mutant human APP-overexpressing transgenic (PDAPP) mice with Aß peptides stimulates the immune system to recognize these peptides and clear them from the neuropil. However, serious concerns regarding the consequences of such an approach in humans have been raised. A principal worry is that active immunization against an endogenous protein in humans could result in a detrimental autoimmune response or other complications in a percentage of the clinical AD population.

Bard et al. provide both a test of the validity of antibody-driven Aß clearance using passive immunization, and an alternative to vaccination as a therapeutic approach to immune-mediated AD therapy (Abstract 397.1). 8-10 month old PDAPP mice received either intraperitoneal anti-Aß antibodies or PBS every week for six months. Normally, PDAPP mice exhibit dramatic Aß accumulation in neuropil plaques by 12-18 months of age; this Aß plaque burden was reduced by over 90% in mice treated with anti-Aß antibodies. Surprisingly, peripherally administered anti-Aß antibodies were found to decorate plaques in treated mice, as demonstrated by immunocytochemistry. Vascular permeability and the concentration of endogenous immunoglobulins were unaltered in the brains of treated mice, suggesting that the blood-brain barrier was intact.

The hypothesized mechanism of immunization- and antibody-stimulated clearance of Aß is via phagocytic brain microglia. The authors tested microglia-mediated Aß clearance in an ex vivo assay, which combined fresh frozen PDAPP mouse cryostat sections with primary mouse microglial cultures. The results of these studies suggest that cultured microglia can effectively phagocytize Aß in tissue sections treated with anti-Aß antibodies that bind plaques in situ, but not in sections treated with control antibodies or anti-Aß antibodies that do not bind plaques in situ. Critically, the authors also show evidence supporting the degradation of phagocytized Aß peptides in this model. In principal, antibody-stimulated Aß clearance by microglial phagocytosis should be dependent on the constant (Fc) region of anti-Aß IgG antibodies. Thus, to further test the hypothesis that Aß clearance in this model is antibody-dependent, the authors investigated the effect of treatment with F(ab’)2 fragments, which contain only the variable (antigen binding) regions of the IgG molecule, in lieu of whole IgG. As predicted, while F(ab’)2 fragments still decorated PDAPP plaques, indicating interaction with accumulated Aß peptides, they were ineffective at promoting Aß clearance by microglial phagocytosis in the ex vivo assay. Hence, these findings point to Fc-receptor-mediated microglial activation as the mechanism of Aß removal.

This study provides a tantalizing view of the potential for therapeutically targeting the immune system to treat AD. Moreover, the ability of therapeutic levels of monoclonal antibodies to enter the central nervous system could have implications for other neurodegenerative diseases that are associated with toxic or abnormal proteins, including Huntington’s disease and the spongiform encephalopathies. Additional studies investigating the clinical applicability of these findings to AD are currently under way, and could provide one of the first treatments aimed at the neuropathological mechanisms underlying dysfunction and degeneration in AD. However, a significant component of the neurodegenerative damage caused by Aß peptides could result from intracellular accumulation, and may be unrelated to plaque deposition in the neuropil . Additionally, APP overexpressing transgenic models do not exhibit gross neuronal loss or the full inflammatory response associated with AD. Thus, the efficacy of such a treatment for stabilizing neurodegenerative changes such as synapse and neuron loss, and the capacity for this strategy to meaningfully stabilizing or improving cognitive function, remain unknown.—Aileen Anderson


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