Transcriptional regulation of the presenilin-1 gene: implication in Alzheimer's disease.
Two (amyloid and presenilin) hypotheses have been proposed to explain the pathogenesis of Alzheimer's disease (AD). According to amyloid hypothesis, the main amyloid plaques which are hallmark of AD are generated by beta- and gamma-secretase mediated proteolytic processing of amyloid precursor protein (APP). The amyloid hypothesis does not adequately address the pathogenesis of the disease, however, since transgenic mice that express the pathologic mutations of the APP and presenilin-1 (PS1) genes produce amyloid plaques but fail to exhibit neurodegeneration and memory loss observed in AD patients. According to presenilin hypothesis, loss of essential functions of PS due to decreased PS expression or mutations in the PS genes better explains the pathogenesis of AD. Recent studies have revealed that forebrain specific conditional knockouts of PS1 and PS2 genes (cPSKO) cause both neuronal degeneration and memory loss without evidence of formation of amyloid plaques. Another potential mechanism for the pathogenesis of AD may reside at the transcriptional regulation of the presenilin-1 gene. In this review, a detailed analysis of transcription factors that regulate PS1 transcription will be discussed. An in depth understanding of the regulatory mechanism of PS1 transcription can identify the targets that can potentially be used in therapeutic intervention of AD.
Das
Hriday K
HK
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas 76107, USA. hdas@hsc.unt.edu
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D003704:Dementia / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D053764:Presenilin-1 / Q000096:biosynthesis* / Q000235:genetics*; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D053764:Presenilin-1; D014157:Transcription Factors