BACKGROUND: Retinal 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-beta (Abeta) 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. METHODS: Eyes 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 Abeta, whereas Abeta 42/40 levels were assayed by ELISA. APP and processed fragments were detected biochemically by Western blotting with domain-specific antibodies, using antibody WO2 (Abeta) and rabbit antibody 369 to the C-terminal domain of APP. RESULTS: Immunocytochemistry revealed strong cytoplasmic expression of APP and possibly Abeta 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 alpha-secretase generated C-terminal fragments in transgenic retinal tissues than beta-secretase-generated C-terminal fragments. Very low level Abeta was detected in transgenic retinas by ELISA; retinal Abeta 42 was 75 times less than for transgenic brain. Abeta was not detected in mouse retina by Western blotting in our study, indicating much less generation of Abeta in retina than brain tissue. CONCLUSIONS: Alzheimer's mouse model retinas present with different APP proteolytic products and have a significantly lower production of amyloidogenic Abeta than found in brain.
BACKGROUND: Retinal 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-beta (Abeta) 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. METHODS: Eyes 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 Abeta, whereas Abeta 42/40 levels were assayed by ELISA. APP and processed fragments were detected biochemically by Western blotting with domain-specific antibodies, using antibody WO2 (Abeta) and rabbit antibody 369 to the C-terminal domain of APP. RESULTS: Immunocytochemistry revealed strong cytoplasmic expression of APP and possibly Abeta 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 alpha-secretase generated C-terminal fragments in transgenic retinal tissues than beta-secretase-generated C-terminal fragments. Very low level Abeta was detected in transgenic retinas by ELISA; retinal Abeta 42 was 75 times less than for transgenic brain. Abeta was not detected in mouse retina by Western blotting in our study, indicating much less generation of Abeta in retina than brain tissue. CONCLUSIONS:Alzheimer'smouse model retinas present with different APP proteolytic products and have a significantly lower production of amyloidogenic Abeta than found in brain.
Authors: G Prihar; A Verkkoniem; J Perez-Tur; R Crook; S Lincoln; H Houlden; M Somer; A Paetau; H Kalimo; A Grover; L Myllykangas; M Hutton; J Hardy; M Haltia Journal: Nat Med Date: 1999-10 Impact factor: 53.440
Authors: Lee E Goldstein; Julien A Muffat; Robert A Cherny; Robert D Moir; Maria H Ericsson; Xudong Huang; Christine Mavros; Jennifer A Coccia; Kyle Y Faget; Karlotta A Fitch; Colin L Masters; Rudolph E Tanzi; Leo T Chylack; Ashley I Bush Journal: Lancet Date: 2003-04-12 Impact factor: 79.321
Authors: Michelle T Fodero-Tavoletti; David P Smith; Catriona A McLean; Paul A Adlard; Kevin J Barnham; Lisa E Foster; Laura Leone; Keyla Perez; Mikhalina Cortés; Janetta G Culvenor; Qiao-Xin Li; Katrina M Laughton; Christopher C Rowe; Colin L Masters; Roberto Cappai; Victor L Villemagne Journal: J Neurosci Date: 2007-09-26 Impact factor: 6.167
Authors: Yosef Koronyo; David Biggs; Ernesto Barron; David S Boyer; Joel A Pearlman; William J Au; Shawn J Kile; Austin Blanco; Dieu-Trang Fuchs; Adeel Ashfaq; Sally Frautschy; Gregory M Cole; Carol A Miller; David R Hinton; Steven R Verdooner; Keith L Black; Maya Koronyo-Hamaoui Journal: JCI Insight Date: 2017-08-17
Authors: Harald Hampel; Nicola Toschi; Claudio Babiloni; Filippo Baldacci; Keith L Black; Arun L W Bokde; René S Bun; Francesco Cacciola; Enrica Cavedo; Patrizia A Chiesa; Olivier Colliot; Cristina-Maria Coman; Bruno Dubois; Andrea Duggento; Stanley Durrleman; Maria-Teresa Ferretti; Nathalie George; Remy Genthon; Marie-Odile Habert; Karl Herholz; Yosef Koronyo; Maya Koronyo-Hamaoui; Foudil Lamari; Todd Langevin; Stéphane Lehéricy; Jean Lorenceau; Christian Neri; Robert Nisticò; Francis Nyasse-Messene; Craig Ritchie; Simone Rossi; Emiliano Santarnecchi; Olaf Sporns; Steven R Verdooner; Andrea Vergallo; Nicolas Villain; Erfan Younesi; Francesco Garaci; Simone Lista Journal: J Alzheimers Dis Date: 2018 Impact factor: 4.472