Exacerbation of Cerebral Amyloid Angiopathy-Associated Microhemorrhage in Amyloid Precursor Protein Transgenic Mice by Immunotherapy Is Dependent on Antibody Recognition of Deposited Forms of Amyloid β

Abstract

Passive immunization with an antibody directed against the N terminus of amyloid ␤ (A␤) has recently been reported to exacerbate cerebral amyloid angiopathy (CAA)-related microhemorrhage in a transgenic animal model. Although the mechanism responsible for the deleterious interaction is unclear, a direct binding event may be required. We characterized the binding properties of several monoclonal anti-A␤ antibodies to deposited A␤ in brain parenchyma and CAA. Biochemical analyses demonstrated that the 3D6 and 10D5, two N-terminally directed antibodies, bound with high affinity to deposited forms of A␤, whereas 266, a central domain antibody, lacked affinity for deposited A␤. To determine whether 266 or 3D6 would exacerbate CAA-associated microhemorrhage, we treated aged PDAPP mice with either antibody for 6 weeks. We observed an increase in both the incidence and severity of CAA-associated microhemorrhage when PDAPP transgenic mice were treated with the N-terminally directed 3D6 antibody, whereas mice treated with 266 were unaffected. These results may have important implications for future immune-based therapeutic strategies for Alzheimer's disease.

Amyloid-β vaccination, but not nitro-nonsteroidal anti-inflammatory drug treatment, increases vascular amyloid and microhemorrhage while both reduce parenchymal amyloid

“…We have previously shown that this phenomenon is occurring following passive immunization with Aβ antibodies (Wilcock et al, 2004c). Other groups have also shown that treatment of aged APP transgenic mice with anti-Aβ antibodies results in an increased incidence of vascular microhemorrhage (Pfeifer et al, 2002;Racke et al, 2005). However, to date, this vascular adverse event has not been reported following active immunization.…”

“…Immunization by the same protocol also prevented cognitive deficits in both doubly transgenic APP+PS1 mice (Morgan et al, 2000) and CRND8 transgenic APP mice (Janus et al, 2000). It was later shown that passive immunization of transgenic mice using anti-Aβ antibodies resulted in significant reductions in amyloid deposition (Bard et al, 2000;Wilcock et al, 2004b), but also increased incidence of microhemorrhage (Pfeifer et al, 2002;Racke et al, 2005) associated with increased cerebral amyloid angiopathy (CAA) (Wilcock et al, 2004c).…”

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

“…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.…”

“…Recent preclinical studies illustrate that passive immunizations with antibodies that target amyloid plaques and reverse the cognitive deficit also increase CAA in transgenic mouse models of AD (21,22). In addition, CAA-associated microhemorrhages were augmented with such immunizations in transgenic AD models (21)(22)(23)(24). These effects of anti-A␤ immunotherapy present a significant risk in light of the fact that CAA is associated with pathological abnormalities and cognitive impairment in the elderly population, and is prevalent in Ͼ80% of patients with AD (25,26).…”

Nasal inoculation of an adenovirus vector encoding 11 tandem repeats of Aβ1‐6 upregulates IL‐10 expression and reduces amyloid load in a Mo/Hu APPswe PS1dE9 mouse model of Alzheimer's disease

“…Another possible side effect associated with Aβ vaccination is cerebral hemorrhages that were reported in one of AD patients subjected to the AN1792 clinical trial. Several groups [70][71][72] reported that passive immunization of anti-Aβ antibodies directed against N-terminal epitopes of Aβ and/or antibodies immunoreactive with Aβ deposits increased cerebral microhemorrhage in AD mouse models. This hemorrhage seems to be associated with passive immunization but not with active one [22].…”