ABSTRACT
Accumulating evidence indicates that mutations in the presenilin 1 (PS1) gene are responsible for most cases of familial Alzheimer's disease (AD). Although its biological functions are not yet fully understood, it appears that PS1 plays a role in the processing and trafficking of the amyloid precursor protein (APP). However, little is known about factors that are involved in regulating the metabolism of PS1 especially in relation to AD pathology. In this study, we have examined the effect of optic nerve crush, intravitreal injection of the inflammatory agent lipopolysaccharide (LPS) or injection of amyloid beta(1-42) (A beta(1-42)) on the expression and processing of PS1 in the rat retina. We found that 48 h after injection of A beta(1-42) there was a dramatic alteration in the banding pattern of PS1 on Western blots, as indicated by marked changes in the levels of expression of some of its C- and N-terminal fragments in retinal homogenates. These results suggest an A beta(1-42)-induced potentiation of a non-specific stress-related but inflammation-independent alteration of processing of PS1 in this in vivo model.
Subject(s)
Amyloid beta-Peptides/pharmacology , Gene Expression Regulation/drug effects , Peptide Fragments/pharmacology , Presenilin-1/metabolism , Retina/drug effects , Animals , Female , Gene Expression Regulation/physiology , Inflammation/chemically induced , Inflammation/metabolism , Lipopolysaccharides/pharmacology , Optic Nerve Injuries/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
Presenilin 1 (PS1) is a multitransmembrane protein well known for being mutated in most cases of familial Alzheimer's disease. Although its pathological effect is clear, its biological functions are not yet fully understood, but it appears to be involved in development and apoptosis. To investigate the role of PS1 in developmental processes we have studied the expression and proteolytic processing of this protein in the developing rat retina. PS1 appears to be developmentally regulated in the retina, and the pattern of PS1 immunoreactivity is consistent with a role in retinal lamination and pattern formation. Interestingly, no correlation was observed between PS1-positive cells and cells undergoing programmed cell death, suggesting that PS1 does not play a role in apoptosis occurring during this period. Moreover, we observed a change in the pattern of PS1 proteolytic fragments suggestive of a novel alternative cleavage site in the PS1 molecule.
Subject(s)
Alternative Splicing , Gene Expression Regulation, Developmental/physiology , Membrane Proteins/metabolism , Retina/metabolism , Animals , Animals, Newborn , Apoptosis/physiology , Humans , Hydrolysis , Membrane Proteins/genetics , Presenilin-1 , Rats , Rats, Sprague-Dawley , Retina/chemistry , Retina/embryology , Retina/growth & development , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
We have studied the neurotoxicity of amyloid-beta (Abeta) after a single unilateral intravitreal injection. Within the retina apoptotic cells were seen throughout the photoreceptor layer and the inner nuclear layer but not in the ganglion cell layer at 48 h after injection of Abeta(1-42) compared to vehicle control and control peptide. At 5 months, there was a significant reduction in total cell numbers in the ganglion cell layer in Nissl stained retinas. There was glial cell dysfunction with upregulation of glial fibrillary acidic protein and a reduction in the expression of Müller cell associated proteins in the injected retinas. These results suggest an indirect cytotoxic effect of Abeta on retinal neurons and an important role for dysfunction of Müller glia in mediating Abeta neurotoxicity.
