ABSTRACT
Alzheimer's disease (AD) is a devastating neurodegenerative disorder that results in loss of memory and cognitive function, eventually leading to dementia. A key neuropathological event in AD is the cerebral accumulation of senile plaques formed by aggregates of amyloid-ß-peptides (Aß). Aß results from two sequential endoproteolytic cleavages operated on the amyloid-ß precursor protein (AßPP), an integral membrane protein with a single-membrane spanning domain, a large extracellular N-terminus and a shorter, cytoplasmic C-terminus. First, ß-secretase (BACE1) cleaves AßPP at the N-terminal end of the Aß sequence to produce a secreted form of AßPP, named sAßPP, and a C-terminal membrane-bound 99-aminoacid fragment (C99). Then, γ-secretase cleaves C99 within the transmembrane domain to release the Aß peptides of different lengths, predominantly Aß1-40 and Aß1-42.
Subject(s)
Alzheimer Disease/genetics , Amyloid Precursor Protein Secretases/genetics , Amyloid beta-Protein Precursor/genetics , Aspartic Acid Endopeptidases/genetics , Brain/enzymology , RNA, Messenger/biosynthesis , Transcription, Genetic , Alzheimer Disease/enzymology , Alzheimer Disease/pathology , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Protein Precursor/metabolism , Aspartic Acid Endopeptidases/metabolism , Brain/pathology , Humans , Peptide Fragments/genetics , Peptide Fragments/metabolism , Plaque, Amyloid/enzymology , Plaque, Amyloid/genetics , Plaque, Amyloid/pathology , Protein Structure, Tertiary , Proteolysis , RNA Processing, Post-Transcriptional , RNA, Messenger/genetics , Signal TransductionABSTRACT
Recently, we showed that oxidative stress activates the expression and activity of the beta-site AbetaPP-cleaving enzyme (BACE), an aspartyl protease responsible for the beta-secretase cleavage of AbetaPP. The identification of compounds able to prevent the induction of this event is an important goal of therapeutic strategies for Alzheimer's disease (AD). Dehydroepiandrosterone (DHEA) is an adrenal steroid that improves a variety of functions in the central nervous system. Moreover, a series of evidence suggests that DHEA displays antioxidant properties in different experimental models. In the present paper we show that pretreatment with DHEA is able to rescue the increase of mRNA expression, protein levels, and activity of BACE, produced by oxidative stress in NT2 neurons. BACE, being the enzyme that initiates the production of Abeta, is a drug target for AD. Our results imply that DHEA administration may slow down the AD pathological process, lowering Abeta accumulation.
