doi:10.1016/j.expneurol.2004.12.015 
Copyright © 2004 Elsevier Inc. All rights reserved.
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
Wen-Feng Yua, 1, Zhi-Zhong Guana, 1, Nenad Bogdanovicb, c and Agneta Nordberga, c, 
, 
aDivision of Molecular Neuropharmacology, Neurotec Department, Karolinska Institutet, Karolinska University Hospital Huddinge, B84, S-141 86 Stockholm, Sweden
bDivision of Experimental Geriatrics, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden
cDepartment of Geriatric Medicine, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden
Received 2 July 2004;
revised 9 December 2004;
accepted 10 December 2004.
Available online 26 January 2005.
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Abstract
In the present study, we have investigated the expression of nicotinic acetylcholine receptors (nAChRs) on astrocytes and neurons in the hippocampus and temporal cortex of subjects carrying the Swedish amyloid precursor protein (APP) 670/671 mutation (APPswe), patients with sporadic Alzheimer's disease (AD), and age-matched control subjects. Significant increases in the total numbers of astrocytes and of astrocytes expressing the α7 nAChR subunit, along with significant decreases in the levels of α7 and α4 nAChR subunits on neurons, were observed in the hippocampus and temporal cortex of both APPswe and sporadic AD brains. Both of these phenomena were more pronounced in APPswe than sporadic AD cases. Furthermore, the number of [125I]α-BTX binding sites (α7 nAChR) in the temporal cortex of the APPswe brain was significant lower than in the younger control group, reflecting the lower neuronal level of α7 nAChR. The increase in the level of expression of α7 nAChR on astrocytes was positively correlated with the extent of neuropathological alternations, especially the number of neuritic plaques, in the AD brain. The elevated expression of α7 nAChR on astrocytes might participate in Aβ cascade and formation of neuritic plaques, thereby playing an important role in the pathogenesis of AD.
Keywords: Alzheimer's disease; APPswe mutation; Astrocytes; Immunohistochemistry; Nicotinic receptors
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Fig. 1. Expression of the α7 nAChR subunit on astrocytes and neurons in the brains of Alzheimer patients carrying the APPswe mutation or affected with sporadic AD, as well as of age-matched control individuals. Double immunolabeling for GFAP (brown) and α7 nAChR (blue) (A) and for GFAP (brown) and α4 nAChR (blue) (B) demonstrated that only the α7 subunit was expressed on astrocytes. Double immunolabeling for Aβ (brown) and α7 nAChRs (blue) (C) showed α7 nAChR-positive astrocytes surrounding neuritic plaques. α7 nAChR-expressing astrocytes and neurons were detected in the CA1 region of the hippocampus of control subjects (D), sporadic AD patients (E) ,and APPswe patients (F); as well as in layer V of the temporal cortex of control subjects (G), sporadic AD patients (H), and APPswe patients (I). In panels D–I, both α7-positive astrocytes and neurons are stained brown and the arrows indicate α7-positive astrocytes. Scale bar = 20 μm in A–C. Scale bar = 40 μm in D–I. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 2. The percentages of α7 nAChR-positive astrocytes in the hippocampus and temporal cortex from APPswe, sporadic AD patients, and age-matched control subjects. (A) The percentages of astrocytes in CA1, CA2, and CA3 regions of the hippocampus that stained positive for α7 nAChR. (B) The percentages of α7 nAChR-positive astrocytes in the upper (I–III) and deep (IV–VI) layers of the temporal cortex. The results are expressed as the percentage of astrocytes expressing α7 nAChR subunit in the total number of astrocytes. *P < 0.05, **P < 0.01 as compared to the age-matched control groups; and #P < 0.05, ##P < 0.01 as compared to sporadic AD, by using ANOVA followed by post hoc test.
Fig. 3. Double immunolabeling of Aβ (brown) and α7 nAChR (blue) in AD brains. The astrocytes expressing α7 nAChR surrounded or lie in the vicinity of neuritic plaques (large arrows) in both APPswe (A) and sporadic AD (B) brains; with only a few positive astrocytes being seen near the diffuse plaques (small arrows) in sporadic AD (C). Scale bar = 40 μm. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 4. Statistically significant positive correlations between the percentage of astrocytes expressing α7 nAChR and the numbers of neuritic plaques per mm2 in the hippocampus (A) and temporal cortex (B); and the number of neurofibrillary tangles in the CA1 region of the hippocampus (C) in the AD patients. Linear regression analysis on the combined values for both APPswe and sporadic AD patients was performed employing the correlation Z test.
Fig. 5. The number of α7 nAChR-positive neurons in the hippocampus and temporal cortex of APPswe and sporadic AD patients in relationship to age-matched control subjects. (A) α7 nAChR-positive neurons in the CA1, CA2, and CA3 regions of the hippocampus. (B) The α7 nAChR-positive neurons in the upper (I–III) and deep (IV–VI) layers of the temporal cortex. The results are expressed as the percentage of the mean value for the younger control group (which was designated as 100%). **P < 0.01 compared to the age-matched control subjects; #P < 0.05 as compared to the sporadic AD group, as analyzed using the ANOVA followed by post hoc test.
Fig. 6. The numbers of α4 nAChR-positive neurons in the hippocampus and temporal cortex from APPswe and sporadic AD patients in relationship to age-matched control subjects. (A) α4 nAChR-positive neurons in the CA1, CA2, and CA3 regions of the hippocampus. (B) α4 nAChR-positive neurons in the upper (I–III) and deep (IV–VI) layers of the temporal cortex. The results are expressed as the percentage of the mean value for younger control group (100%). **P < 0.01 as compared to the age-matched control subjects; and ##P < 0.01 as compared to sporadic AD group, as analyzed by the ANOVA followed by post hoc test.
Table 1.
Summary of the clinical and neuropathological characteristics of the subjects
APPswe, AD patients carrying Swedish APP 670/671 mutation; NPs, neuritic plaques; NTs, neurofibrillary tangles; CA1, in hippocampus; Temp, temporal cortex. Values are expressed as the mean ± SD.
* P < 0.05.
** P < 0.01 when compared to the sporadic AD employing Mann–Whitney test.
Table 2.
[125I]α-BTX binding sites of the temporal cortex in Alzheimer patients with the APPswe mutation, sporadic AD, and from age-matched control subjects
APPswe, AD patients carrying the Swedish APP 670/671 mutation. The values presented represent the mean ± SD.
* P < 0.01 compared to the younger group as analyzed employing the ANOVA followed by post hoc test.
Table 3.
The numbers of astrocytes in different regions of the brains of APPswe and sporadic AD patients and of age-matched control subjects
Astrocytes were identified by specific immunohistochemical staining for GFAP. APPswe, AD patients carrying the Swedish APP670/671 mutation AD; “a” and “b” stand for P < 0.05 compared to the age-matched control group, and “c” for P < 0.05 compared to the sporadic AD group, according to the ANOVA followed by post hoc test.
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