Amyloid precursor protein processing and retinal pathology in mouse models of Alzheimer’s disease View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2009-03-07

AUTHORS

R. Michael Dutescu, Qiao-Xin Li, Jonathan Crowston, Colin L. Masters, Paul N. Baird, Janetta G. Culvenor

ABSTRACT

BackgroundRetinal ganglion cell loss is considered to be a cause of visual impairment in Alzheimer`s patients. Alterations in amyloid precursor protein (APP) processing and amyloid-β (Aβ) accumulation, key molecules associated with Alzheimer`s disease pathogenesis, may therefore contribute to retinal damage. We therefore investigated retinal APP processing and eye morphology in Alzheimer`s transgenic mouse models.MethodsEyes and brain samples of 2- to 18-month-old transgenic mice expressing human APP with the double Swedish mutation (APPswe) (APP K595N/M596L)(Tg2576) were compared with eyes and brain tissue from wild-type background C57BL6xSJL controls. In addition, 6- to 12-month-old double transgenic mice over-expressing human APPswe and mutant presenilin 1 with exon 9 deletion (APPswe/PS1-dE9) were compared with background controls of C57BL6xC3H strain. Tissue samples were fixed in formalin for immunohistochemistry, and dissected retinal and cerebellar extracts were frozen for Western blotting and enzyme-linked immunosorbent assay (ELISA). Monoclonal antibodies 1E8 and WO2 were used for immunohistochemical detection of APP and Aβ, whereas Aβ 42/40 levels were assayed by ELISA. APP and processed fragments were detected biochemically by Western blotting with domain-specific antibodies, using antibody WO2 (Aβ) and rabbit antibody 369 to the C-terminal domain of APP.ResultsImmunocytochemistry revealed strong cytoplasmic expression of APP and possibly Aβ in retinal ganglion cells and inner nuclear layer cells, and in lens and corneal epithelia for APP transgenic mice. Retinas from the APP transgenic mouse strains contained 18 to 70 kDa APP proteolytic products that were not detected in the cerebellum. We found a higher proportion of APP α-secretase generated C-terminal fragments in transgenic retinal tissues than β-secretase-generated C-terminal fragments. Very low level Aβ was detected in transgenic retinas by ELISA; retinal Aβ 42 was 75 times less than for transgenic brain. Aβ was not detected in mouse retina by Western blotting in our study, indicating much less generation of Aβ in retina than brain tissue.ConclusionsAlzheimer’s mouse model retinas present with different APP proteolytic products and have a significantly lower production of amyloidogenic Aβ than found in brain. More... »

PAGES

1213-1221

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00417-009-1060-3

DOI

http://dx.doi.org/10.1007/s00417-009-1060-3

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1000939912

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/19271231


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86 detection
87 different APP proteolytic products
88 disease
89 disease pathogenesis
90 domain
91 domain-specific antibodies
92 double Swedish mutation
93 double transgenic mice
94 enzyme-linked immunosorbent assay
95 epithelium
96 exon 9 deletion
97 expression
98 extract
99 eye morphology
100 eyes
101 formalin
102 fragments
103 ganglion cell loss
104 ganglion cells
105 generation
106 higher proportion
107 human APP
108 human APPswe
109 immunohistochemical detection
110 immunohistochemistry
111 immunosorbent assay
112 impairment
113 inner nuclear layer cells
114 key molecules
115 layer cells
116 lens
117 less generation
118 level Aβ
119 levels
120 loss
121 low level Aβ
122 low production
123 mice
124 model
125 model retina
126 molecules
127 morphology
128 mouse model
129 mouse retina
130 mouse strains
131 mutant presenilin 1
132 mutations
133 nuclear layer cells
134 pathogenesis
135 pathology
136 patients
137 precursor protein processing
138 presenilin 1
139 processing
140 production
141 products
142 proportion
143 protein processing
144 proteolytic products
145 retina
146 retinal APP processing
147 retinal Aβ 42
148 retinal damage
149 retinal ganglion cells
150 retinal pathology
151 retinal tissue
152 samples
153 secretase
154 strains
155 strong cytoplasmic expression
156 study
157 terminal domain
158 terminal fragment
159 time
160 tissue
161 tissue samples
162 transgenic brains
163 transgenic mice
164 transgenic mouse model
165 transgenic mouse strain
166 transgenic retinal tissues
167 transgenic retinas
168 visual impairment
169 wild-type background C57BL6xSJL controls
170 ’s mouse model retinas
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