9 December 2011. Despite clinical setbacks, lowering brain amyloid or soluble Aβ remains a popular approach for tackling Alzheimer’s disease. The main push comes in the form of small-molecule and immunotherapies developed in pharma companies. But at the Society for Neuroscience 2011 annual meeting, held 12-16 November in Washington, DC, numerous scientists also presented academic work in this area. Here follows a couple of strategies, including a new amyloid immunization strategy and an unusual attempt to clear brain amyloid with radiation.
The potential of the immune system to clear amyloid has caught the eye of many researchers, with more than a dozen anti-amyloid vaccination strategies currently in clinical trials. One potential drawback of active immunization is possible autoimmune side effects. At last year’s SfN, Charlie Glabe at the University of California, Irvine, talked about immunizing mice with a short peptide, called 3A, that forms β-sheet oligomers and stimulates an immune response specific for oligomeric forms of Aβ. Because 3A is not part of the human genome, it is unlikely to cause autoimmune effects, Glabe said. Back then, he reported that 3xTg mice vaccinated with 3A have fewer plaques and better cognitive function than unvaccinated ones. At this year’s meeting, Suhail Rasool, a postdoctoral researcher working with Glabe, presented new work extending the findings to Tg2576 mice. Rasool told ARF he chose these animals because, unlike the triple transgenics, they develop neuroinflammation and neuronal loss. This allowed the researchers to look more closely at the vaccine’s effect on inflammation.
Rasool compared vaccination with 3A peptide to vaccination with synthetic oligomers or fibrillar forms of Aβ. He injected the antigens subcutaneously every month from three to 14 months. The 3A oligomer was as effective as Aβ oligomers or fibrils in lowering soluble Aβ and amyloid plaque load, Rasool reported. At 14 months, immunized mice performed better in the water maze, object recognition tests, and passive inhibitory avoidance than unimmunized controls. Compared to controls, immunized mice produced less CD45, a marker of inflammation that is elevated in AD brain, and fewer activated astrocytes in the cortex and hippocampus, showing that the treatment quieted inflammation. Although most of these results were similar in all immunized animals, soluble Aβ42 fell only in mice immunized with 3A, not those treated with oligomeric or fibrillar Aβ. The data have been submitted for publication, Rasool noted. In future work, the authors would like to test 3A vaccination in an α-synuclein mouse model, as the immune response may also attack oligomeric forms of this protein.
If immunization approaches seem a dime a dozen, and you hunger for a new idea out of left field, then how about irradiating the skull? In a poster session, Daniel Michael at Beaumont Hospital, Royal Oak, Michigan, detailed early results from X radiation therapy in AD mouse models. If radiation seems far-fetched, it is in AD, but radiation has been used successfully to treat human systemic amyloidosis, Michael claimed (see Kurrus et al., 1998; Monroe et al., 2004; Poovaneswaran et al., 2008). Coauthor James Fontanesi, a radiation oncologist, wondered whether this treatment could also clear brain amyloid in APPSwe/PS1deltaE9 animals. They compared several different dosage amounts and protocols, from a single treatment of five, 10, or 15 grays (Gy), to a “fractionated” protocol where mice received one Gy for 10 days in a row, or two Gy for five consecutive days. (A “gray” is a unit of absorbed radiation equal to one joule of radiation absorbed by one kilogram of tissue, or 100 rad.) These dosages are similar to those used to treat the brains of children with leukemia who go on to have normal life expectancies, Michael told ARF, and, hence, are considered safe. In support of this, pathological examination showed little brain damage in the irradiated mice, and similar numbers of healthy neurons in treated and untreated brain regions.
The researchers irradiated one side of the brain and compared the number of amyloid plaques with those on the untreated side at two, four, and eight weeks after treatment. They reported that both the single and fractionated protocols reduced the number and size of plaques equally, with higher radiation doses being more effective than lower ones. Plaque number dropped further after eight weeks than after shorter intervals, implying that plaques continued to be cleared after dosing stopped. For example, mice treated with 15 Gy had an average of 40 percent fewer plaques in treated regions at two weeks post-treatment, and almost 70 percent fewer at eight weeks out. Michael said he does not know how radiation might reduce plaques, but hypothesizes that it stimulates local microglia and astrocytes, which then clear deposits. The researchers saw some evidence of increased levels of inflammatory mediators such as TNFα, IL10, and IL1β in treated brain regions, Michael said. In ongoing studies, the authors are testing cognition in treated mice and determining how long the effects they have seen to date will last.—Madolyn Bowman Rogers.