Do natural antibodies prevent Alzheimer disease?

Britschgi, M. et al. Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decreases with normal aging and advancing Alzheimer's disease. Proc. Natl Acad. Sci. USA 106, 12145–12150 (2009).

Extracellular amyloid plaques, which are formed through accumulation and aggregation of amyloid-β (Aβ) peptide, are one of the pathological hallmarks of Alzheimer disease (AD). Much research within the AD field is underpinned by the premise that preventing formation of these plaques should alleviate the clinical symptoms of the disease. Tony Wyss-Coray and colleagues have demonstrated that healthy individuals have a range of natural antibodies against known toxic Aβ peptides and other amyloidogenic non-Aβ species. The levels of some of these antibodies decline with age and AD progression, suggesting that immunization strategies could provide a prophylactic treatment for AD.

Antibodies against Aβ peptide have been detected, albeit at low titers, in blood and cerebrospinal fluid (CSF) from individuals both with and without overt AD symptoms. This observation, coupled with evidence from animal research, as well as clinical trials indicating that immunization against Aβ peptide can reduce both plaque load within the brain and cognitive deficiencies, makes the use of vaccines an attractive prospect for the treatment of AD. “Most studies measured only antibodies against full-length synthetic Aβ peptides,” notes Wyss-Coray. “Because the majority of Aβ isolated from human brains appears to be post-translationally modified, truncated and present in various states of assembly, we decided ... to measure autoantibodies against these different species of Aβ, ” he goes on to explain.

By incubating human plasma samples and CSF with Aβ peptide and related amyloid species on peptide microarrays, Wyss-Coray and colleagues demonstrated the abundant existence of antibodies to amyloid peptides. These antibodies were present in both patients with AD and healthy controls. High titers of antibodies recognizing oligomeric assemblies of Aβ and oxidized forms were evident. In stark contrast, however, antibodies recognizing non-aggregated Aβ_1–40 or Aβ_1–42, or unmodified Aβ, were present only at low titers. More surprising, however, was the fact that immunoreactivity to mutant forms of Aβ peptide, which are only found in rare familial cases of dementia and are not present in the general population, was evident in the study population, including healthy controls. It seems likely, therefore, that the antibodies are cross-reactive and recognize various forms of Aβ and related amyloidogenic peptides. Furthermore, “antibodies are present at young age decades before typical onset of AD, arguing strongly against Aβ deposited in AD brains as the trigger for these antibodies,” comments Wyss-Coray. Importantly, some antibodies were most abundant in young individuals and declined with age, and to a lesser extent with disease severity, suggesting that immunotherapy in the elderly could be beneficial.

To examine the physiological relevance of the identified antibodies, in vitro experiments were performed to test the ability of these antibodies to protect neurons from Aβ toxicity. Purified antibodies obtained from three different plasma samples were shown to protect primary hippocampal neurons from Aβ-evoked cell death, and to increase cell viability, when the antibodies were preincubated with Aβ_1–42. Furthermore, the ability of the three antibody samples to protect neurons from Aβ-induced cell death was shown to be equal to that of monoclonal antibodies raised against Aβ.

To further test the physiological relevance of the identified antibodies, the researchers conducted immunization trials in vervets. These animals have been shown to develop features of AD in old age, and amyloid plaques can be identified within their brains. Using the same peptide microarray technique that was used to identify antibodies in their study participants, Wyss-Coray and colleagues demonstrated that vervets had similar antibody profiles to humans. Furthermore, immunization with full-length human Aβ peptide was shown to markedly clear cerebral amyloid plaques from the vervet brains, and to induce a substantial corresponding increase in cross-reactive antibodies to toxic Aβ peptide and amyloidogenic non-Aβ species.

This research demonstrates that humans have a broad repertoire of antibodies against Aβ peptide and related peptide species from an early age. Some of these antibodies are cross-reactive and levels of these antibodies decline with age. According to Wyss-Coray, “our work ... supports the idea that non-Aβ peptides could be used for active immunotherapy,” and a future immunization program based on these findings could prove to be beneficial. In the immediate future, however, “we would like to carry out longitudinal studies in healthy individuals and determine if people who later develop AD have reduced levels or certain patterns of autoantibodies,” states Wyss-Coray.