Amyloid-β Peptide Remnants in AN-1792-Immunized Alzheimer's Disease Patients

Abstract

Experiments with amyloid-␤ (A␤)-42-immunized transgenic mouse models of Alzheimer's disease have revealed amyloid plaque disruption and apparent cognitive function recovery. Neuropathological examination of patients vaccinated against purified A␤-42 (AN-1792) has demonstrated that senile plaque disruption occurred in immunized humans as well. Here, we examined tissue histology and quantified and biochemically characterized the remnant amyloid peptides in the gray and white matter and leptomeningeal/cortical vessels of two AN-1792-vaccinated patients, one of whom developed meningoencephalitis. Compact core and diffuse amyloid deposits in both vaccinated individuals were focally absent in some regions. Although parenchymal amyloid was focally disaggregated, vascular deposits were relatively preserved or even increased. Immunoassay revealed that total soluble amyloid levels were sharply elevated in vaccinated patient gray and white matter compared with Alzheimer's disease cases. Our experiments suggest that although immunization disrupted amyloid deposits, vascular capture prevented largescale egress of A␤ peptides. Trapped, solubilized amyloid peptides may ultimately have cascading toxic effects on cerebrovascular, gray and white matter tissues. Anti-amyloid immunization may be most effective not as therapeutic or mitigating measures but as a prophylactic measure when A␤ deposition is still minimal. This may allow A␤ mobilization under conditions in which drainage and degradation of these toxic peptides is efficient.

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

“…Our results not only help to better define the mechanisms underlying immunotherapy-induced changes in amyloid, but also point to icv delivery as a superior therapeutic route for delivering anti-A␤ antibodies to the brain that can significantly reverse behavioral deficits and reduce AD-related pathological changes, and importantly, also reduce CAA and associated micro-hemorrhages. We used a mouse monoclonal IgG 1 , 6E10, that recognizes the N terminus of human A␤ and binds to the monomer, parenchymal plaques, and CAA (19,32,33). In this respect, the A␤-binding properties of 6E10 are similar to the properties of anti-A␤ antibodies generated in subjects immunized with AN1972 in the aforementioned active immunotherapy trial (14,34,35).…”

“…The discontinued phase II trial of active immunization with aggregated A␤ as an immunogen (AN1792) along with the QS-21 adjuvant demonstrated some clinical benefit in AD subjects who developed a robust anti-A␤ antibody response (14,15). The autopsy reports of 4 subjects from this trial who survived up to 20 months after their first immunization revealed focal clearance of parenchymal plaques in the cortex (16)(17)(18)(19). In contrast, the accumulation of amyloid in cerebral blood vessels, also known as cerebral amyloid angiopathy (CAA), was more severe than observed in non-immunized patients at a similar stage of AD, with multiple cortical hemorrhages evident in one case (17,19,20).…”

“…The autopsy reports of 4 subjects from this trial who survived up to 20 months after their first immunization revealed focal clearance of parenchymal plaques in the cortex (16)(17)(18)(19). In contrast, the accumulation of amyloid in cerebral blood vessels, also known as cerebral amyloid angiopathy (CAA), was more severe than observed in non-immunized patients at a similar stage of AD, with multiple cortical hemorrhages evident in one case (17,19,20). 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).…”

“…Given the likelihood that immunotherapy-solubilized amyloid redistributes from the parenchymal plaques to the cerebral vasculature (19,21,47), it is possible that the amyloid clearance from prolonged icv infusions of low-dose anti-A␤ antibodies is sufficiently gradual that it fails to substantially accumulate in the cerebral vasculature and result in CAA. We aimed to test this hypothesis by delivering bolus icv injections of relatively high doses of anti-A␤ antibodies to briefly flood the CSF and maximize the movement of antibody into the parenchyma for clearance of amyloid (48,49).…”

“…Treatment-induced changes in amyloid accumulation were quantified using a series of sections, per mouse brain, stained with the Campbell-Switzer protocol to reveal diffuse as well as dense-core fibrillar parenchymal plaques (19,39,40). In the transgenic mice treated with control IgG 1 , plaques were abundant throughout the cerebral cortex (Fig.…”