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The Accumulation of Aβ Deposits in the Retinas of APPswe/PS1 Transgenic Mice with Retinal Functional Degeneration |
Zhizhang Dong1, Juan Li2, Xuerong Sun3, Jian Ge4 |
1The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
2Department of Ophthalmology, the Fourth Hospital of Xi'an, Xi'an 710004, China
3Institute of Aging, Guangdong Medical University, Dongguan 523000, China
4State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China |
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Abstract Objective: To conduct research on Alzheimer's disease (AD) that is specifically focused on retinal functional and structural changes in TgAPPswePS1 transgenic mice; to demonstrate the role amyloid beta(Aβ) plays in retinal dysfunction; to provide new in sight into retinal AD pathology. Methods: APPswe/PS1 bigenic mice about 24 months of age (experimental group) and non-transgenic littermates about 24 months of age (control group) were grouped for experiments. The eyes of the TgAPPswePS1 mice were examined with electroretinography (ERG). The change in retinal morphology was investigated, while the expressions of the amyloid precursor protein (APP) and Aβ were examined with immunohistochemistry using retinal sections. All of the results were quantified and statistically analyzed by a student's t test. Results: In the experimental group, the rod response, which showed a reduction of the amplitudes of both a and b waves, was compared to the control group. The difference in the b wave amplitude was statistically significant
(t=5.23, P=0.002). For maximum response amplitudes, both flash-triggered a waves and b waves showed a striking decrease compared to the control group. The difference in the a and b waves was statistically significant (t=15.69, 15.76, P<0.001). There were no significant structural abnormalities in the retinal
sections in either the experimental or control groups. We found a decrease in the thickness of the retina in the experimental group compared to the controls, but the the difference was not statistically significant(t=1.85, P=0.087). In the experimental group, APP immunoreactivity was predominantly detected in the
cytoplasm of cells in the ganglion cell layer as well as the inner nuclear layer. By comparison, a much lower staining intensity was observed in the control group in the corresponding regions of the retina. The Aβ accumulation in the retina could be detected by a diffuse pattern and plaque deposits. A majority of
the Aβ-immunoreactive plaques were detected from the ganglion cell layer to the inner plexiform layer, the outer nuclear layer, and even in the photoreceptor outer segment layer. However, no Aβ positive immunoreactivity was detected in the retinas of mice in the control group. Conclusions: Aβ deposits
accumulate in the retina of aged TgAPPswePS1 mice, which is associated with retinal degenerative changes in both function and structure. This suggests that AD-related pathology changes in the retina may contribute to the visual deficits seen in AD.
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Received: 23 October 2017
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Fund: National Natural Science Foundation of China (81371007, 81400424); Science and Technology Research and Development Project of Shaanxi Province (2014K11-03-07-04); Science and Technology Research Project of Wenzhou (Y20140140) |
Corresponding Authors:
Jian Ge, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China (Email: gejian@mail.sysu.edu.cn)
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|
[1] |
Palop JJ, Mucke L. Amyloid-beta-induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nat Neurosci, 2010, 13(7): 812-818. DOI: 10.1038/nn.2583.
|
[2] |
Castellani RJ, Smith MA. Compounding artefacts with uncertainty, and an amyloid cascade hypothesis that is "too big to fail". J Pathol, 2011, 224(2): 147-152. DOI: 10.1002/path.2885.
|
[3] |
Rizzo M, Anderson SW, Dawson J, et al. Vision and cognition in Alzheimer's disease. Neuropsychologia, 2000, 38(8): 1157-1169.
|
[3] |
Rizzo M, Anderson SW, Dawson J, et al. Vision and cognition in Alzheimer's disease. Neuropsychologia, 2000, 38(8): 1157-1169.
|
[4] |
Guo L, Duggan J, Cordeiro MF. Alzheimer's disease and retinal neurodegeneration. Curr Alzheimer Res, 2010, 7(1): 3-14.
|
[5] |
Perez SE, Lumayag S, Kovacs B, et al. Beta-amyloid deposition and functional impairment in the retina of the APPswe/PS1DeltaE9 transgenic mouse model of Alzheimer's disease.Invest Ophthalmol Vis Sci, 2009, 50(2): 793-800. DOI: 10.1167/iovs.08-2384.
|
[6] |
Dutescu RM, Li QX, Crowston J, et al. Amyloid precursor protein processing and retinal pathology in mouse models of Alzheimer's disease. Graefes Arch Clin Exp Ophthalmol, 2009,247(9): 1213-1221. DOI: 10.1007/s00417-009-1060-3.
|
[4] |
Guo L, Duggan J, Cordeiro MF. Alzheimer's disease and retinal neurodegeneration. Curr Alzheimer Res, 2010, 7(1): 3-14.
|
[5] |
Perez SE, Lumayag S, Kovacs B, et al. Beta-amyloid deposition and functional impairment in the retina of the APPswe/PS1DeltaE9 transgenic mouse model of Alzheimer's disease.Invest Ophthalmol Vis Sci, 2009, 50(2): 793-800. DOI: 10.1167/iovs.08-2384.
|
[6] |
Dutescu RM, Li QX, Crowston J, et al. Amyloid precursor protein processing and retinal pathology in mouse models of Alzheimer's disease. Graefes Arch Clin Exp Ophthalmol, 2009,247(9): 1213-1221. DOI: 10.1007/s00417-009-1060-3.
|
[7] |
Ning A,Cui J, To E,et al. Amyloid-beta deposits lead to retinal degeneration in a mouse model of Alzheimer disease. Invest Ophthalmol Vis Sci, 2008, 49(11): 5136-5143. DOI:10.1167/iovs.08.1849.
|
[8] |
Yin H, Chen L, Chen X, et al. Soluble amyloid beta oligomers may contribute to apoptosis of retinal ganglion cells in glaucoma.Med Hypotheses, 2008, 71(1): 77-80. DOI: 10.1016/j.mehy.2008.01.030.
|
[9] |
Dong Z, Li J, Leng Y, et al. Cyclic intensive light exposure induces retinal lesions similar to age-related macular degeneration in APPswe/PS1 bigenic mice. BMC Neurosci, 2012, 13: 34. DOI:10.1186/1471-2202-13-34.
|
[10] |
卢艳, 唐娜, 王蓉. APP/PS1 双转基因阿尔茨海默病模型小鼠视网膜神经节细胞丢失的初步观察. 中华眼科杂志, 2012,48(9): 836-841. DOI: 10.3760/cma.j.issn.0412-4081.2012.09.
|
[7] |
Ning A,Cui J, To E,et al. Amyloid-beta deposits lead to retinal degeneration in a mouse model of Alzheimer disease. Invest Ophthalmol Vis Sci, 2008, 49(11): 5136-5143. DOI:10.1167/iovs.08.1849.
|
[8] |
Yin H, Chen L, Chen X, et al. Soluble amyloid beta oligomers may contribute to apoptosis of retinal ganglion cells in glaucoma.Med Hypotheses, 2008, 71(1): 77-80. DOI: 10.1016/j.mehy.2008.01.030.
|
[9] |
Dong Z, Li J, Leng Y, et al. Cyclic intensive light exposure induces retinal lesions similar to age-related macular degeneration in APPswe/PS1 bigenic mice. BMC Neurosci, 2012, 13: 34. DOI:10.1186/1471-2202-13-34.
|
[10] |
卢艳, 唐娜, 王蓉. APP/PS1 双转基因阿尔茨海默病模型小鼠视网膜神经节细胞丢失的初步观察. 中华眼科杂志, 2012,48(9): 836-841. DOI: 10.3760/cma.j.issn.0412-4081.2012.09.
|
|
015.
|
|
015.
|
[11] |
Volianskis A, Kostner R, Molgaard M, et al. Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the
|
[11] |
Volianskis A, Kostner R, Molgaard M, et al. Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the
|
|
APPswe/PS1deltaE9-deleted transgenic mice model of ss-amyloidosis. Neurobiol Aging, 31(7): 1173-1187. DOI:10.1016/j.neurobiolaging.2008.08.005.
|
|
APPswe/PS1deltaE9-deleted transgenic mice model of ss-amyloidosis. Neurobiol Aging, 31(7): 1173-1187. DOI:10.1016/j.neurobiolaging.2008.08.005.
|
[12] |
Hsiao K, Chapman P, Nilsen S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science, 1996, 274(5284): 99-102.
|
[13] |
Li J, Dong Z, Liu B, et al. Hypoxia induces beta-amyloid in association with death of RGC-5 cells in culture. Biochem Biophys Res Commun, 2011, 410(1): 40-44. DOI: 10.1016/
|
[12] |
Hsiao K, Chapman P, Nilsen S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science, 1996, 274(5284): 99-102.
|
[13] |
Li J, Dong Z, Liu B, et al. Hypoxia induces beta-amyloid in association with death of RGC-5 cells in culture. Biochem Biophys Res Commun, 2011, 410(1): 40-44. DOI: 10.1016/
|
|
j.bbrc.2011.05.101.
|
[14] |
Jen LS, Hart AJ, Jen A, et al. Alzheimer's peptide kills cells of retina in vivo. Nature, 1998, 392(6672): 140-141. DOI: 10.1038/
|
|
j.bbrc.2011.05.101.
|
[14] |
Jen LS, Hart AJ, Jen A, et al. Alzheimer's peptide kills cells of retina in vivo. Nature, 1998, 392(6672): 140-141. DOI: 10.1038/
|
32 |
321.
|
[15] |
刘超启, 孙哲, 曹立宁, 等. 小鼠视网膜下注射淀粉样蛋白β(1-42)后视网膜组织的变化. 中华眼科杂志, 2015, 51(11): 831-838. DOI: 10.3760/cma.j.issn.0412-4081.2015.11.008.
|
[16] |
Aruoma OI, Jen SS, Watts HR, et al. Acute and chronic effects of intravitreally injected beta-amyloid on the neurotransmitter system in the retina. Toxicology, 2009, 256(1-2): 92-100. DOI:10.1016/j.tox.2008.11.007.
|
[17] |
Shimazawa M, Inokuchi Y, Okuno T, et al. Reduced retinal function in amyloid precursor protein-over-expressing transgenic mice via attenuating glutamate-N-methyl-d-aspartate receptor signaling. J Neurochem, 2008, 107(1): 279-290. DOI: 10.1111/j.1471-4159.2008.05606.x.
|
[18] |
Hoh Kam J, Lenassi E, Jeffery G,et al. Viewing ageing eyes:diverse sites of amyloid Beta accumulation in the ageing mouse retina and the up-regulation of macrophages. PloS one, 2010,5(10): e13127. DOI: 10.1371/journal.pone.0013127.
|
32 |
321.
|
[15] |
刘超启, 孙哲, 曹立宁, 等. 小鼠视网膜下注射淀粉样蛋白β(1-42)后视网膜组织的变化. 中华眼科杂志, 2015, 51(11): 831-838. DOI: 10.3760/cma.j.issn.0412-4081.2015.11.008.
|
[16] |
Aruoma OI, Jen SS, Watts HR, et al. Acute and chronic effects of intravitreally injected beta-amyloid on the neurotransmitter system in the retina. Toxicology, 2009, 256(1-2): 92-100. DOI:10.1016/j.tox.2008.11.007.
|
[17] |
Shimazawa M, Inokuchi Y, Okuno T, et al. Reduced retinal function in amyloid precursor protein-over-expressing transgenic mice via attenuating glutamate-N-methyl-d-aspartate receptor signaling. J Neurochem, 2008, 107(1): 279-290. DOI: 10.1111/j.1471-4159.2008.05606.x.
|
[18] |
Hoh Kam J, Lenassi E, Jeffery G,et al. Viewing ageing eyes:diverse sites of amyloid Beta accumulation in the ageing mouse retina and the up-regulation of macrophages. PloS one, 2010,5(10): e13127. DOI: 10.1371/journal.pone.0013127.
|
|
|
|