People produce different antibodies to different antigens, and those with Alzheimer's disease (AD) are no exception. Can those antibodies tell us something about the disease—even suggest a therapy? Possibly both, according to new data. Writing in the June 18 Archives of Neurology, researchers led by Pierre Aucouturier, St-Antoine Hospital, Paris, France, report that patients with a variant of Alzheimer’s—posterior cortical atrophy with evidence of AD—have lower titers of anti-Aβ antibodies than do healthy controls or people with typical AD. The work hints that biomarker heterogeneity may reflect underlying pathological differences. Other research suggests that some people with AD who make natural antibodies to ankyrin G stabilize or even improve their cognitive scores over two years, while patients without ankyrin G antibodies decline. Ankyrin G is a cytoskeletal, cytoplasmic protein that can end up in amyloid plaques. The anchor protein may even be a therapeutic target, suggest researchers led by Roger Nitsch, University of Zurich, Switzerland, in a Molecular Psychiatry paper published June 12.
As reported in the Nitsch paper, joint first authors Antonella Santuccione Chadha, Mario Merlini, and Aparna Shetty looked in older adults for antibodies that may alter the course of AD. They took serum from 15 people with late-onset AD and from 10 age- and sex-matched controls. All completed the Mini-Mental State Exam (MMSE) at baseline and study's end—up to 28 months later. Antibodies against ankyrin G, which anchors voltage-gated channels to axon initial segments, turned up in many of those with AD. Further tests of 31 AD patients and 33 healthy controls showed that about half of those with AD and a quarter of normal controls produce anti-ankyrin G antibodies. After two years, AD patients who carried the antibodies performed as well, or even better, on the MMSE than at baseline, while patients without the antibody declined on average about five points. The findings suggest that these antibodies protect against disease progression.
This study may help explain why the gene coding ankyrin G, ANK3, was identified as a potential risk factor for late-onset AD (see Morgan et al., 2008). To delve deeper, Santuccione Chadha and colleagues used immunochemistry to examine the protein in the brains of people both with and without AD. Not only did they find ankyrin G associated with extracellular plaques, but AD brains had much more of the anchor in the cortex than controls.
How might this normally cytoplasmic protein get deposited outside the neuron? The answer could lie in exosomes. Ankyrin G turned up in exosomal fractions in human kidney cells and neuroblastoma cells, raising the possibility that these packets release the protein into the extracellular space. Nitsch and colleagues propose that once excreted, ankyrin G becomes a self-antigen and leads to antibodies. Since the protein is embedded in plaques, ankyrin antibodies might encourage plaque clearance and confer protection.
To test this, the researchers actively immunized 14-week-old transgenic ArcAβ mouse lines and controls against ankyrin G. After 16 weeks, insoluble Aβ40 and Aβ42 fell in the brain, whereas soluble forms rose. More antibodies glommed onto ankyrin G in plaques with cumulative immunization doses and microglia surrounded plaques in immunized mice. The findings suggest that the anti-ankyrin G antibodies may have guided the glia to plaques. If true, that suggests ankyrin G antibodies could be a potential therapeutic. Monoclonal antibodies isolated from immunized mice restored synaptic spines when applied to hippocampal slices from ArcAβ animals. However, after testing the mice in a Y-maze, the researchers saw no behavioral benefits for immunized mice.
"Maybe the pathology was already too advanced to be rescued in terms of behavior," said Santuccione Chadha. It is also possible that toxic Aβ42 solubilized from plaques masked any cognitive benefit, she said, but argued that since the antibodies restored dendritic spines in hippocampal slices, that pathology was likely ameliorated in the mice. "We may have a tool in hand to produce a different vaccine against Alzheimer's disease." she said. Nitsch is cofounder of Neurimmune Holding AG, which specializes in identifying vaccines for neurodegenerative diseases.
"It is fair to say that this is a new potential target for vaccination, which usually focuses on Aβ," said Markus Mandler, AFFiRiS AG, Vienna, Austria. Norman Relkin, Weill Cornell Medical College, New York City, agreed that it is an interesting observation. "This is a clever use of immunology to define potential new Alzheimer's treatment targets," he said. However, he suggested that more experiments need to be done. For one thing, antibody titers (rather than just immunopositivity) should be measured in a prospective study with a predefined cutoff for positivity, he said. The research group should also look at other antibodies in the same subjects to determine whether this particular antibody rises specifically or whether it is elevated as part of a non-specific immune dysregulation in certain AD patients, he added.
Could anti-ankyrin G antibodies be key to the intravenous immunoglobulin (IVIG) cocktail currently in clinical trials (see ARF related news story)? IVIG is derived from young, healthy plasma donors and may contain different antibodies than are present in disease states such as Alzheimer's, Relkin said. "I wouldn't predict that IVIG would have high levels of this antibody since these investigators report that older, age-matched controls have low levels compared to Alzheimer's patients." Further investigation will be needed to determine levels in younger people and in IVIG, he suggested.
Aucouturier and his group are taking a similar approach, in that they are looking at the difference between antibodies in two different types of dementia. First author Guillaume Dorothée enrolled 13 patients with typical AD and eight with posterior cortical atrophy (PCA). In this form of dementia, plaques and tangles are present, but the pathology starts earlier and is focused in the posterior cortices. Twelve healthy volunteers acted as age-matched controls.
Plaque levels (as revealed by PET imaging) and CSF biomarkers (including calculated ratios) were pretty much the same among patients. However, total serum anti-Aβ antibody levels were lower in people with PCA than those with AD or healthy controls. Differences were especially obvious in immunoglobulin G1 and G3 subclasses. One possibility is that disparate levels of antibodies reflect different levels of soluble Aβ monomers or oligomers between the diseases, suggested the authors. Fewer anti-Aβ antibodies in PCA patients could also indicate more efficient recruitment of anti-Aβ-bearing monocytes to the central nervous system, or weaker anti-Aβ immune responses. Regardless of the cause, AD may present itself in distinct ways depending on those antibody differences, the authors wrote.—Gwyneth Dickey Zakaib
- Morgan AR, Hamilton G, Turic D, Jehu L, Harold D, Abraham R, Hollingworth P, Moskvina V, Brayne C, Rubinsztein DC, Lynch A, Lawlor B, Gill M, O'Donovan M, Powell J, Lovestone S, Williams J, Owen MJ. Association analysis of 528 intra-genic SNPs in a region of chromosome 10 linked to late onset Alzheimer's disease. Am J Med Genet B Neuropsychiatr Genet. 2008 Sep 5;147B(6):727-31. PubMed.
- Morgan AR, Turic D, Jehu L, Hamilton G, Hollingworth P, Moskvina V, Jones L, Lovestone S, Brayne C, Rubinsztein DC, Lawlor B, Gill M, O'Donovan MC, Owen MJ, Williams J. Association studies of 23 positional/functional candidate genes on chromosome 10 in late-onset Alzheimer's disease. Am J Med Genet B Neuropsychiatr Genet. 2007 Sep 5;144B(6):762-70. PubMed.
- Nitsch RM, Hock C. Targeting beta-amyloid pathology in Alzheimer's disease with Abeta immunotherapy. Neurotherapeutics. 2008 Jul;5(3):415-20. PubMed.
- Bennett V, Healy J. Organizing the fluid membrane bilayer: diseases linked to spectrin and ankyrin. Trends Mol Med. 2008 Jan;14(1):28-36. PubMed.
- Santuccione AC, Merlini M, Shetty A, Tackenberg C, Bali J, Ferretti MT, McAfoose J, Kulic L, Bernreuther C, Welt T, Grimm J, Glatzel M, Rajendran L, Hock C, Nitsch RM. Active vaccination with ankyrin G reduces β-amyloid pathology in APP transgenic mice. Mol Psychiatry. 2013 Mar;18(3):358-68. PubMed.
- Dorothée G, Bottlaender M, Moukari E, de Souza LC, Maroy R, Corlier F, Colliot O, Chupin M, Lamari F, Lehéricy S, Dubois B, Sarazin M, Aucouturier P. Distinct Patterns of Antiamyloid-β Antibodies in Typical and Atypical Alzheimer Disease. Arch Neurol. 2012 Sep 1;69(9):1181-5. PubMed.