Peter (133.3) compared full-length Aβ1-42 with the amino-terminal fragment Aβ1-7, and passive immunization with monoclonals either against plaques (the 3D6) or against soluble Aβ (the m266 antibody). The Elan group still considers vaccines that trigger microglial phagocytosis most efficient, as both passive administration of 3D6 and active treatment with the small N-terminal Aβ fragment cleared amyloid pathology. A second presentation by Elan scientists (201.13) showed that AD patients in the AN-1792 trial had produced antibodies mainly against the first nine amino-terminal residues of Aβ, again suggesting the peptide’s C-terminus is dispensable for a strong humoral response.
As expected, the m266 antibody did not clear plaque deposits; this implies that rapid improvements in a learning task seen with this antibody occur because it interferes with acute effects of soluble Aβ, perhaps on synapses (see ARF related news story). Other scientists speculated that soluble Aβ might explain the day-to-day variations in cognition frequently seen in AD patients, rather than the gradual decline over time. Several groups presented work on antibodies which appear to be oligomer-specific and could remove soluble pools of Aβ. While such novel antibodies could yield rapid effects on cognition, the studies have not yet clearly demonstrated that these antibodies are specific to Aβ. Further research must show that they don’t cause problems by interacting with other physiological proteins that can oligomerize, such as insulin.
The m266 antibody has gained fame also because it fueled the peripheral sink hypothesis of AD vaccination, which holds out hope that passive immunization could “draw” out brain Aβ (see ARF related news story). This study raised a question about the staying power of this effect; in other words, can plasma Aβ increases after an antibody injection really predict future decreases in brain Aβ? Addressing this issue was a longitudinal study by the research collaboration between Steven Paul, Ron DeMattos at Eli Lilly and Company in Indianapolis, Dave Holtzman at Washington University, St. Louis, and colleagues. The scientists injected m266 into APPV717F mice at four and eight months of age, measured their plasma Aβ levels the next day, let them age, and at 12 months quantified their amyloid burden immunohistochemically. Results differed somewhat between Aβ42 and 40, but overall, the scientists reported that relative increases in plasma Aβ soon after immunization indeed correlated with, i.e., predicted, amyloid burden in the hippocampus and cortex at an older age (842.19).
Pritam Das and VG Howard, working with Todd Golde at the Mayo Clinic in Jacksonville, Florida, reported that passive immunization with an unusual antibody that recognizes the C-terminal end of soluble Aβ (most antibodies bind the other end) effectively reduced brain levels of Aβ40 and 42, while increasing plasma levels 25-fold. An ongoing longitudinal study will address cognitive effects, if any, pathology, and possible mechanisms (133.13).
Cindy Lemere’s group at Brigham and Women’s Hospital, Boston, presented the latest data on their immunization of the Caribbean vervet monkeys, following her presentation at last year’s CSH meeting (scroll to Lemere in ARF related news story). There, Lemere had reported high antibody titers and reductions in CSF Aβ after immunizing five aged monkeys with Aβ42. In New Orleans, Lemere reported that brain levels of insoluble Aβ42 were reduced by two-thirds in the immunized monkeys, while soluble Aβ40 levels were unchanged. Brains of immunized monkeys contained no Aβ42-immunoreactive plaques in six regions checked, but controls did (133.5). These results recapitulate results in mice and make this non-human primate an alternative model for vaccine development and other AD studies. The monkeys contained no tangles but did have hyperphosphorylated tau in neurites near plaques, Lemere said. The next immunization study will assess cognition in the monkeys before and after treatment. Lemere’s lab also presented characterizations of the mouse immune response following intranasal vaccination, and reported that genetic background and choice of adjuvant can greatly influence the nature of the immune response to immunization with Aβ and its peptide fragments (201.1, 201.11), suggesting that choice of adjuvant may be key in developing the human vaccine, too (see also Furlan et al., 2003).
Einar Sigurdsson and colleagues at New York University School of Medicine reported that a modified version of their K6Aβ1-30 vaccine (see ARF related news story), in which a hydrophobic region around amino acid 18 and 19 was altered, improved the performance of Tg2576 mice in the radial arm maze, even though antibody titers were low and the amyloid burden shrank only modestly, affecting only small plaques. The work suggests that massive amyloid clearance and high titers may not be necessary for a therapeutic effect (133.10).
Though approaches vary, it appears that the strongest benefit to date lies in preventing future deposition and mild cognitive improvement in older animals with severe deposition; neuritic plaques generally stay in place. No new trials were officially announced, though speculation was rampant. This news summary can’t be comprehensive. My apologies to all whose work went unmentioned; as always, I encourage additions and corrections. You can view abstracts mentioned in this story at the SfN/ScholarOne website.—Gabrielle Strobel.