Original ArticlesNeuroautoantibody immunoreactivity in relation to aging and stress in apolipoprotein E-deficient mice
Introduction
Apolipoprotein E (ApoE) polymorphism is a major genetic risk factor for the complex neurodegenerative disorder of Alzheimer’s disease (AD; for reviews see 7, 18). In addition to genetic factors, environmental stress and autoimmune abnormalities may play a role in the progression of AD, and it has been proposed that AD is related to the failure to adapt to chronic stress [3]. This is supported by findings of a correlation between AD and elevated levels of stress hormones [23] and with a decreased peripheral glucocorticoid sensitivity [9]. Chronic stress-induced or age-related elevation of glucocorticoid levels can lead to neuronal death and degeneration in the central nervous system (CNS) 12, 19, a major pathological feature associated with cognitive impairment in AD [18]. Another proposed mechanism contributing to the age-related neurodegeneration in AD is a cell-specific attack by autoantibodies against the CNS 8, 20, 21, 25. The age-associated pathogenesis, including autoimmunity, has been correlated with a progressive disruption in both the neuroendocrine and immune systems [14].
Studies using an animal model for investigating the role of ApoE in AD have demonstrated cognitive impairments and neurodegeneration in mice lacking ApoE 6, 10, 11, 28. In addition to memory impairment, an altered corticosterone response to stress has been observed in ApoE-deficient mice 5, 28. Mechanisms leading to memory impairment and altered stress responsiveness are still far from clear, but it has been well demonstrated in other models that cognitive impairment can result from overexposure to stress which induces an elevated level of stress hormones (for reviews see 13, 22, 24). Stress can also cause a rise in autoantibody levels in the serum [1]. In ApoE-deficient mice, memory loss is thought to be associated with early neurodegeneration due to the lack of a neurotrophic effect of ApoE [11]. A recent report has demonstrated that accumulation of β-amyloid-like protein in astrocytes in the hippocampal region can be found as early as 4 weeks of age in ApoE-deficient mice but is not observed in wild-type control mice until they are over 6 months old [17]. Such β-amyloid-induced neurotoxicity may cause neuronal cell damage and degeneration (for review [2]), leading to a disruption of neuronal functional integrity and an up-regulation of autoimmune activities. This was indirectly supported by demonstrations of a higher frequency of CD4+ T cells in ApoE-deficient mice at 9–16 weeks of age [27] and by an altered stress response and impaired memory in these mice at ∼12 weeks of age [28]. It is still unknown whether the observed abnormalities in stress response and autoimmunity occur in ApoE-deficient mice at a very young age and whether there are autoantibodies immunoreactive with the brain in the ApoE-deficient mice.
The main objective of the present study was to investigate neuroautoimmune activities in ApoE-deficient mice of different ages. We examined titers of autoantibodies in relation to stress and age, tissue distribution of the autoantigens, and major components of brain cells recognized by autoimmune sera from ApoE-deficient mice. In addition, we measured serum corticosterone concentration to determine if 7- to 8-week-old ApoE-deficient mice had the same alterations in corticosterone responses to stress as that reported for older mice 5, 28.
Section snippets
Animals and serum collection
Male, ApoE-deficient (C57BL/6J homozygous mice for Apoetm1Unc mutation; knockout) and their wild-type control mice were purchased from Jackson Laboratory (Bar Harbor, ME, USA). In this study, adequate measures were taken to minimize pain and discomfort of animals, and the experiments were conducted in accordance with national legislation and with the National Institutes of Health guide regarding the care and use of animals for experimental procedures. All mice were singly housed and given 7
Results
Autoimmune reactivities of the sera from both age groups of mice against brain antigens determined by ELISA are shown in Fig. 1. Both age groups of ApoE-deficient mice appeared to have higher titers of autoantibodies than wild-type controls, based on differences in the normalized absorbance using the two-way ANOVA of overall effects of genotypes (Age-Group 1: df = 24, F = 6.818, p = 0.014; Age-Group 2: df = 24, F = 7.007, p = 0.014). There was no overall effect of stress on antibody titers
Discussion
The ApoE-deficient mouse has been used as an animal model for studying the relationship between ApoE and AD. It has been shown that ApoE-deficiency in mice results in cognitive impairments and CNS neurodegeneration, which are pathological features seen in patients with AD 6, 10, 11, 28. In a previous study, we reported an impaired spatial memory and an altered corticosterone response to stress in young ApoE-deficient mice at ∼12 weeks of age, suggesting a disruption of functional integrity of
Acknowledgements
This study was supported by a grant from the US Army (DAMD 17-97-2-7013).
References (28)
- et al.
Stress-adaptation failure hypothesis of Alzheimer’s disease
Med. Hypotheses
(1990) - et al.
Evidence for normal aging of the septo-hippocampal cholinergic system in apoE(−/−) mice but impaired clearance of axonal degeneration products following injury
Exp. Neurol.
(1998) - et al.
Derangement in stress response of apolipoprotein E-deficient mice
Neurosci. Lett.
(1996) - et al.
Memory deficits and cholinergic impairments in apolipoprotein E-deficient mice
Neurosci. Lett.
(1995) - et al.
Apolipoprotein E and Alzheimer’s diseasea review of recent studies
Pharmocol. Biochem. Behav.
(1997) - et al.
Identification and characterization of an anti-glial fibrillary acidic protein antibody with a unique specificity in a demented patient with an autoimmune disorder
J. Neurol. Sci.
(1997) - et al.
Neurodegeneration in the central nervous system of apoE-deficient mice
Exp. Neurol.
(1995) - et al.
Neurodegeneration and cognitive impairment in apoE-deficient mice is ameliorated by infusion of recombinant apoE
Brain Res.
(1997) The Alzheimer diseases
Curr. Opin. Neurobiol.
(1996)- et al.
Autoantibody reactivity in serum of patients with Alzheimer’s disease and other age-related dementias
Psychiatry Res.
(1996)
The potential role of excessive cortisol induced by HPA hyperfunction in the pathogenesis of depression
Eur. Neuropsychopharmacol
Monoaminergic neurotransmitters, their precursors and metabolites in brains of Alzheimer patients
Neurosci. Lett.
Stress-induced rise in serum anti-brain autoantibody levels in the rat
Intl J. Neurosci.
A potential role for apoptosis in neurodegeneration and Alzheimer’s
Mol. Neurobiol.
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