On this second day of the conference, scientists gave an update on the current status of Aβ vaccination. Since researchers at Elan Pharmaceuticals in 1999 first demonstrated the basic principle to immunize against Aβ in the hope of clearing amyloid plaques, researchers at most Alzheimer's disease research centers as well as most pharmaceutical companies have taken chase, Sangram Sisodia of the University of Chicago told reporters in a press conference today. While Elan is currently conducting a phase two trial of their vaccine, follow-up research there and elsewhere has since largely corroborated the initial findings but also brought up new questions about the mechanism of action and safety of these vaccines.
The approaches involve either injection of various forms of Aβ (active immunization) to stimulate an endogenous immune response or injection of anti-Aβ antibodies (passive immunization.)
Cindy Lemere and coworkers at Brigham and Women's Hospital in Boston reported new data on their efforts to develop a vaccine that could deliver Aβ through the mucosal membranes of the nose. Lemere used E.coli heat-la_ile enterotoxin to boost the antibody titers of APP/PS1-double transgenic mice receiving Aβ nose drops. Lemere reports at the meeting that after eight weeks of twice-weekly immunization, the mice had 75 percent fewer plaques and a 33-fold increase in Aβ levels in the blood. In collaboration with David Holtzman's group at Washington University, Lemere found that peripheral Aβ occurs complexed with antibodies. Ongoing work is looking at clearance of these complexes.
While convenient, this approach raises safety concerns, as do all active immunizations with Aβ. Recent work has indicated that brain Aβ exists in equilibrium with peripheral Aβ that is mediated by diffusion as well as active transport. Hence, Aβ might also enter the brain and exacerbate plaque formation, especially, perhaps, in aging people who frequently do not mount a strong antibody response. Lemere says that her group has addressed this concern." We tried in many different ways to see if the nasally delivered Aβ gets into the brain and were unable to find any evidence that it does," she said (see related news item).
Another safety question that remains to be answered is whether antibody titers can be raised to efficient levels without also inducing a damaging inflammatory response.
Holtzman's group reported earlier this year that injection with a high-affinity Aβ antibody was a way to draw Aβ out of the brain and reduce plaque formation without the antibody actually entering the brain (see related news item). The researchers are now investigating which transporters might be responsible for Aβ transport between the CNS and the periphery.
Researcher led by Gary Arendash at University of South Florida, Tampa, presented follow-up date from earlier work that had found protection from memory loss with active, long-term immunization in seven-month-old PS1/APP double transgenic mice, which have plaques and begin showing signs of memory loss. This year, the scientists asked if short-term immunization could reverse existing memory deficits, so they tested 16-month-old mice, vaccinated, and retested them after two months. First author David Morgan said they found no memory improvement, suggesting that a future human vaccine might be more preventive than therapeutic and should be given to healthy people who are at risk for developing AD. FDA safety requirements for such a vaccine will be very strict.
Contrasting findings came out of a study by Jean Dodart and colleagues at Eli Lilly and Co., who passively immunized, for only six weeks, aged APP transgenic mice that had impaired memory and found that the antibodies did reverse the memory defects without a large reduction of plaques. The results are difficult to reconcile with Arendash et al., in part because different mouse strains and immunization strategies were used. Dodart's data are consistent with a recent line of investigation suggesting that soluble pool of brain Aβ can impair memory,
Brian Bacskai, et al., who use two-photon microscopy to image plaque dynamics in the brains of living mice, have published earlier this year that a variety of antibodies, when applied directly through a hole drilled into the mice's skull, can clear up plaques within three days. At this conference, they report new findings showing that this effect also works with anti-Aβ Fab2 fragments, which lack the antibody's Fc base. This is surprising because the prevailing mechanism for antibody-mediated clearance of plaques holds that microglial receptors bind the Fc portion of the antibodies and then engulf plaques. "Our results suggest that other mechanisms independent of microglia must also be at play," said Bacskai.
In total, more than 20 presentations at this meeting address aspects of immunotherapy against neurodegenerative diseases. One provides indirect evidence in humans. R.C. Dodel et al. at Philips University in Marburg, Germany, purified and characterized naturally occurring anti-Aβ IgG antibodies from human CSF and blood. Moreover, they found decreased Aβ levels in the CSF of patients with neurologic diseases who were being treated with immunoglobulin preparations. The authors suggest that these natural antibodies are involved in normal, day-to-day clearance of Aβ.—Gabrielle Strobel
Bacskai B et al. Multiple mechanisms are involved in clearance of amyloid-b by immunotherapy. Soc Neurosci 2001.
Lemere CA. Immunization of PSAPP mice leads to decreased cerebral Ab and a corresponding increase in serum Ab.
Morgan D et al. Short-term Ab vaccinations bo not improve cognitive performance in aged, cognitively impaired APP+PS1 transgenic mice.
Dodel RC et al. Treatment with Immunoglobulins reduces Ab peptide in human CSF.