Insights into the mechanisms of action of anti‐Aβ antibodies in Alzheimer's disease mouse models

Abstract

A number of hypotheses regarding how anti-Abeta antibodies alter amyloid deposition have been postulated, yet there is no consensus as to how Abeta immunotherapy works. We have examined the in vivo binding properties, pharmacokinetics, brain penetrance, and alterations in Abeta levels after a single peripheral dose of anti-Abeta antibodies to both wild-type (WT) and young non-Abeta depositing APP and BRI-Abeta42 mice. The rapid rise in plasma Abeta observed after antibody (Ab) administration is attributable to prolongation of the half-life of Abeta bound to the Ab. Only a miniscule fraction of Ab enters the brain, and despite dramatic increases in plasma Abeta, we find no evidence that total brain Abeta levels are significantly altered. Surprisingly, cerebral spinal fluid Abeta levels transiently rise, and when Ab:Abeta complex is directly injected into the lateral ventricles of mice, it is rapidly cleared from the brain into the plasma where it remains stable. When viewed in context of daily turnover of Abeta, these data provide a framework to evaluate proposed mechanisms of Abeta attenuation mediated by peripheral administration of an anti-Abeta monoclonal antibody (mAb) effective in passive immunization paradigm. Such quantitative data suggest that the mAbs are either indirectly enhancing clearance of Abeta or targeting a low abundance aggregation intermediate.

Intracerebroventricular amyloid-β antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice

“…Whereas both systemicand icv-delivered anti-A␤ antibodies entered the brain parenchyma, only the systemic-delivered antibodies were detected at substantial levels in the plasma to engage the peripheral sink mechanism. That said, a recent study has suggested that an increase in plasma A␤ (postulated to represent an efflux of cerebral A␤) may simply be caused by an increase in the half-life of plasma A␤ when bound to a systemically administered anti-A␤ antibody (27). Regardless of whether the peripheral sink mechanism mediates the outcomes of systemic anti-A␤ immunotherapy, it is unlikely to play a role in the reduction of parenchymal plaques and CAA by icv-infused anti-A␤ IgG 1 .…”

“…Recent studies have demonstrated a spike in CSF anti-A␤ antibody concentration, which represents only a small fraction (Յ1%) of the plasma concentration achieved following systemic delivery (27,59). In our study, plasma concentrations of Ϸ200 nM were achieved after systemic delivery of 6E10.…”

“…Whereas the small fraction of systemically delivered anti-A␤ antibodies in the CSF may participate in amyloid clearance, antibodies circulating in the vasculature may be responsible for the increase in CAA. Although their overall penetration in the brain is negligible (Յ0.1%) (10,27,29), amyloid-binding anti-A␤ antibodies, when circulating in the vasculature, may be able to associate with CAA (24). Such association could increase with increasing concentrations of antibody in the vasculature and/or increasing levels of preexisting CAA.…”

“…The mechanisms proposed for the effects of anti-A␤ immunotherapy on amyloid accumulation remain elusive, generally relying on systemic regimens that yield high titers of anti-A␤ antibodies in the peripheral circulation (6,27). High antibody titers bind to substantial amounts of A␤ in the bloodstream, which is believed to shift the overall A␤ equilibrium and create a ''peripheral sink'' that facilitates an efflux of A␤ from the brain (11,28).…”

“…High antibody titers bind to substantial amounts of A␤ in the bloodstream, which is believed to shift the overall A␤ equilibrium and create a ''peripheral sink'' that facilitates an efflux of A␤ from the brain (11,28). Further, high doses of antibody in the periphery are required because of the low-level (Յ0.1%) penetration of antibody across the blood-brain barrier to effectively engage the local (i.e., central) mechanisms for clearing the cerebral amyloid (10,27,29). Recent studies demonstrate that a single intracerebroventricular (icv) injection of anti-A␤ antibodies is able to prevent the A␤-induced impairment of synaptic plasticity in the hippocampus (30), and also transiently reverse the memory deficit in a transgenic AD mouse model (31).…”