High selective expression of α7 nicotinic receptors on astrocytes in the brains of patients with sporadic Alzheimer's disease and patients carrying Swedish APP 670/671 mutation: a possible association with neuritic plaques
Introduction
Alzheimer's disease (AD), the most common form of dementia, occurs in both familial and sporadic forms (Mullan et al., 1992, Rocchi et al., 2003, Tandon et al., 2000). The characteristic neuropathological hallmarks of this disease are neuritic plaques and intracellular neurofibrillary tangles (Braak and Braak, 1997). The major component of the neuritic plaques is β-amyloid protein (Aβ), which contains 39–43 amino acids and is derived from the amyloid precursor protein (APP) (Hardy and Selkoe, 2002). Several mutations in genes located on chromosomes 21, 14, 12, and 1 have been identified in families with a history of AD (Selkoe, 2001, Shastry, 1998). A double mutation in codons 670 and 671 of the APP gene on chromosome 21 has been detected in a Swedish family with early-onset familial AD (APPswe) (Mullan et al., 1992) and shown to alter APP metabolism so as to result in an over-expression of Aβ and consequently extensive formation of amyloid plaques (Citron et al., 1992).
The neuronal nicotinic acetylcholine receptors (nAChRs), members of the super-family of ligand-gated ion channels, are involved in a number of important physiological functions of the brain, including cognitive functions such as learning and memory (Paterson and Nordberg, 2000). Research has revealed consistent deficiencies in nAChRs, and especially in the α4 nAChRs, in several regions of the brains of patients with sporadic AD as well as of APPswe family members (Guan et al., 2000, Martin-Ruiz et al., 1999, Marutle et al., 1999, Nordberg, 2001, Nordberg and Winblad, 1986, Nordberg et al., 1995, Warpman and Nordberg, 1995, Wevers et al., 1999, Yu et al., 2003), suggesting that such deficiencies might be an important aspect in the pathogenesis of this disorder (Nordberg, 2001). Furthermore, a selective increase in the proportion of astrocytes expressing α7 nAChR, which might affect Aβ-mediated inflammatory processes, was recently observed in sporadic AD brains (Teaktong et al., 2003).
APPswe brains show more severely neuropathological changes, e.g., larger number of neuritic plaques and intracellular neurofibrillary tangles than are observed in sporadic AD brains (Bogdanovic et al., 2002). In the present study, we have investigated the expression of different nAChR subunits on astrocytes and neurons in the hippocampus and temporal cortex of APPswe and sporadic AD individuals, as well as age-matched controls, employing immunohistochemistry and receptor binding assay. The significantly increased expression of α7 nAChR on astrocytes in the APPswe brain compared to the sporadic AD and control brains observed suggests an important link between this receptor and the enhanced neuropathological changes resulting from the alternation of APP metabolism in APPswe individuals.
Section snippets
Subjects
Autopsy material from human brains was obtained from the Huddinge Brain Bank at Karolinska University Hospital, Sweden. Autopsy samples from the hippocampus and medial gyrus of the temporal cortex were obtained from four AD patients carrying the Swedish APP 670/671 mutation (mean age at death: 63.3 ± 5.3 years, range 56–68 years), as well as from six sporadic AD patients (mean age: 80.5 ± 8.2 years, range 66–89 years), four younger control subjects (mean age: 63.2 ± 2.8 years, range 59–66
Immunohistochemical staining of the different nAChR subunits expressed on astrocytes and neurons
Immunohistochemical staining revealed that the α7 nAChR subunit was strongly expressed on both astrocytes (Fig. 1A) and neurons (Figs. 1D and G), whereas the nAChR α4 subunit was expressed only on neurons (data not shown), but not on astrocytes (Fig. 1B). Similarly, the nAChR α3 and β2 subunits were expressed only on neurons (data not shown).
[125I]α-BTX binding in the temporal cortex of APPswe, sporadic AD, and age-matched control individuals
The number of [125I]α-BTX binding sites (α7 nAChR) in membrane from the temporal cortex of patients carrying the APPswe mutation was significantly lower
Discussion
The α7 nAChR has recently been the focus of much research activity due to the high density in the hippocampus and neocortex, as well as its functional involvement in learning and memory (Meyer et al., 1997, Newhouse et al., 1997, Paterson and Nordberg, 2000). In present study we have demonstrated increased expression of α7 nAChR subunit on astrocytes in the hippocampus and temporal cortex of APPswe and sporadic AD patients, with a larger number of α7-positive astrocytes being observed in the
Acknowledgments
This work was supported financially by grants from the Swedish Medical Research Council (projects no 05817), the Loo and Hans Osterman's Foundation, the Alzheimer Foundation in Sweden, KI Foundations, the Old Servants Foundation, the Gun and Bertil Stohne's Foundation, the Stiftelsen för Gamla Tjänarinnor, the Foundation for Geriatric Diseases at Karolinska Institutet, and the Bank of Sweden Tercentenary Foundation and Swedish Match. We want to thank Marianne Grip for her help with the
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These authors contributed equally to this work.