Autoimmunity in Alzheimer’s disease: increased levels of circulating IgGs binding Aβ and RAGE peptides
Introduction
Alzheimer’s disease (AD) is a progressive neurodegenerative disease affecting nerve cells located within higher cortical centers that ultimately results in impaired cognition, including a gradual decline in memory, judgment, and communication. Neuropathological and genetic data strongly support a primary role for amyloid peptides, particularly amyloid β protein (Aβ), which accumulate as senile plaques in brain parenchyma, in the pathogenesis of AD. Mutations which are located either immediately adjacent to the Aβ cleavage product sequence 1–42 (N or C terminus), or within the Aβ sequence, have been shown to alter the enzymatic processing of amyloid precursor protein in ways that result in increased production of Aβ1–42 or Aβ1–43 (highly self-aggregating and neurotoxic peptides). Simultaneously, the levels of α-secretase-derived amyloid peptides (less self-aggregating), are decreased, with both factors causally linked to certain inherited (and rarer) forms of AD (for review, see [31]).
In the more prevalent late-onset forms of AD, the roles of specific mutations are less obvious, although some risk factors such as the dose of the ApoE4 allele are known. Age is still the most reliable and potent risk factor for late-onset AD. Therefore it is likely that age-dependent processes play an important part in the appearance of specific AD pathology. Monnier et al. [21] proposed that advanced glycation end product (AGE)-mediated cross-linking of long-lived proteins contribute to the age-related decline in the function of cells and tissues with normal aging. Under oxidative conditions, intermediates of glycation can give rise to ε-carboxymethyl lysine, a major glycoxidation product [9]. In addition to glucose, many sugars, sugar phosphates, ascorbic acid, glycoxal and methyl glycoxal have been shown to generate glycation products at a higher rate than glucose. High levels of gene expression coding the receptor for AGEs (RAGE) occur in AD brain within hippocampal pyramidal cells, cortical neurons, glial cells, and white matter [6]. Some evidence exists to suggest that RAGE permits the accumulation, and supports the aggregation of Aβ, resulting in inflammation and cytotoxicity in neuronal cells [15], [37]. RAGE also may represent a key protein involved in mediating the toxic effects of Aβ on microglial cells, possibly by triggering the inflammatory processes and cellular dysfunction that are prominent in AD pathology [20], [37].
These findings have engendered new research into the roles of AGEs and RAGEs in AD pathology [2], [29], [36]. For example, Aβ peptides have been demonstrated to serve as binding ligands for RAGE, inducing a cascade of events leading to the generation of reactive oxygen species in microglial cells [15], [17], [37]. RAGE has been co-localized nearby neuritic plaque deposits, in the cells of Aβ-containing blood vessels, and in endothelial, neuronal and microglial cells in AD brain tissue at concentrations much greater than those of age-matched control-derived tissues [27]. Therefore, humanized monoclonal antibodies specific to RAGE and/or to Aβ peptides could be valuable not only as diagnostic probes, but as potential therapeutic modalities [29].
Previously we immunized mice with an AGE originally derived from purified human brain neurofilament protein [23]. Unexpectedly, the animals generated IgGs against a peptide fragment of the receptor for RAGE, and against human amyloid Aβ peptide, suggesting that the AGE-immunogen bound endogenous circulating RAGE- and Aβ-like peptides, possibly forming complexes with increased immunogenicity. The presence of circulating Aβ-like antibodies in the peripheral blood of AD patients has been previously reported [7], [14], [24], although the titers of these antibodies have not always been correlated specifically with the disease. We report here that by first purifying specific anti-Aβ IgGs from individual samples derived from AD individuals, relatively high levels were expressed relative to controls. Perhaps even more intriguing, as with our earlier studies in the mouse, AD individuals also expressed high levels of anti-RAGE IgGs.
Section snippets
Participants and evaluation
A total of 75 particpants, 33 Alzheimer’s disease (AD) and 42 healthy seniors (controls), were recruited from patients seen at specialized clinics for assessment and management of memory disorders at the Augusta Georgia Veterans Affairs Medical Center (VAMC), Georgia State University, and the Medical College of Georgia Neurological Disease Database Repository (NDDR), a core program of the Alzheimer’s Research Center. Control participants (healthy seniors) were recruited from unaffected blood
Results
Table 1 lists the distribution of various demographic and clinical variables for the AD participants and healthy seniors (controls). There were no statistically significant differences in the distributions of sex, race, family history of AD, or diabetes between AD and control individuals. The distribution of the tertile groups for RAGE and Aβ were different between AD and control individuals with AD individuals tending to be in the higher tertiles than the control individuals for both the RAGE
Discussion
There is evidence that the immune system plays a protective role in AD. Microglial cells can degrade Aβ peptides, and recent studies suggest that auto-reactive Aβ presenting T cells may be relevant to the peripheral elimination of the peptide [34]. In the early stages of AD the immune system appears to play a supportive role in the elimination of amyloid peptides. During the course of disease progression, failure to eliminate toxic Aβ peptides along with activation of the innate immune system
Acknowledgements
This work was supported by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs, and by the Medical College of Georgia Combined Intramural Grant Program. The authors would like to thank Dr. David M. Stern, Dean, School of Medicine and Dr. Jeffery L. Rausch, Professor of Psychiatry and Health Behavior at the Medical College of Georgia for their helpful comments and insights regarding this work.
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