Abstract
Abstract: :
Purpose: Cataract and Alzheimer's disease (AD) are characterized by protein aggregation. ß-amyloid (Aß) pathophysiology contributes to senile cataract and neurodegeneration. The ß-site Alzheimer precursor protein (APP)-cleaving enzymes (BACE 1&2) are ß-secretases (proteases) that cleave APP at the N-terminus site releasing deleterious Aß peptides. Bace 2 and APP occur on the Down Syndrome (DS) critical region of human chromosome 21 and mouse 16. Neprilysin (NEP), the primary ß-amyloid degrading enzyme in AD, is down regulated with aging. NEP, also known as Common Acute Lymphocytic Leukemia (ALL) Antigen 10 or CD10, is linked with ALL in DS and somatic trisomy 21. We examined the expression of BACE 1&2 and NEP in normal and cataractous rodent lenses that may affect Alzheimer pathophysiology in cataract formation as they do in AD neurodegeneration. Methods: RT-PCR, western blot and immunohistochemistry were used in order to detect BACE 1, 2 and NEP in rodent lenses. Quantitative expression in cataractous and normal lenses was determined. Results: BACE 1, 2 and Neprilysin are expressed in lenses at the mRNA and protein level. BACE and NEP expression overlaps with Aß in rodent lenses. We demonstrate that BACE 1 and NEP mRNA alternative splicing patterns, previously considered diagnostic of neuronal cell expression, also occurs in the lens. Conclusion: The overlap of BACE 1, 2, NEP and Aß expression suggests these protease contribute to regulation of ß-amyloid production in normal and pathological lenses. Lens alternative splicing patterns previously detected only in neurons provides further examples of similar gene regulation in lens and neurons. BACE and NEP proteases may contribute to Alzheimer and oxidative stress-related lens degeneration that we demonstrated in our previous AD-related models of cataract formation.
Keywords: 338 cataract • 527 protein structure/function • 530 proteolysis