Lens defects and age-related fiber cell degeneration in a mouse model of increased AbetaPP gene dosage in Down syndrome.
Early-onset cataract and Alzheimer's disease occur with high frequency in Down syndrome (trisomy 21), the most common chromosome duplication in human live births. Previously, we used in vivo and lens organ culture models to demonstrate Alzheimer pathophysiology in oxidative stress-related lens degeneration. Currently, well-characterized Alzheimer transgenic mouse models are used to extend these findings. Here, we report on mice carrying a complete copy of a wild-type human AbetaPP (hAbetaPP) gene from the Down syndrome critical region on chromosome 21. hAbetaPP mice produce fiber cell membrane defects similar to those described in human cataracts and increased age-related lens degeneration. hAbetaPP expression and mRNA alternative splicing in human and mouse lens and cornea favor longer, potentially more amyloidogenic forms. Endogenous mouse AbetaPP expression is increased in transgenic lenses, consistent with the cycle of oxidative stress proposed in the mechanism of Alzheimer pathophysiology. Alternative splicing previously designated as neuron-specific occurs in human lens and cornea, and is maintained by hAbetaPP expressed in mouse tissues. These present data implicate AbetaPP in fiber cell formation and in early-onset cataracts in Down syndrome. Finally, our findings provide further support for our hypothesis that Alzheimer pathophysiology contributes to the cataract formation that is increasing in the aging population.
Frederikse
Peter H
PH
Department of Pharmacology and Physiology, Rutgers/UMDNJ Integrative Neurosciences Program, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 185 S. Orange Avenue, MSB H-645 Newark, NJ 07103, USA. frederph@umdnj.edu
Ren
Xiao-Ou
XO
D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002386:Cataract / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D002891:Chromosomes, Human, Pair 21; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics* / Q000473:pathology*; D018628:Gene Dosage; D006801:Humans; D007908:Lens, Crystalline / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019076:Transgenes
D016564:Amyloid beta-Protein Precursor