Targeting BACE with small inhibitory nucleic acids - a future for Alzheimer's disease therapy?

• Authors: Barbara Nawrot
• Languages of publication: EN

Abstracts

EN

β-Secretase, a β-site amyloid precursor protein (APP) cleaving enzyme (BACE), participates in the secretion of β-amyloid peptides (Aβ), the major components of the toxic amyloid plaques found in the brains of patients with Alzheimer's disease (AD). According to the amyloid hypothesis, accumulation of Aβ is the primary influence driving AD pathogenesis. Lowering of Aβ secretion can be achieved by decreasing BACE activity rather than by down-regulation of the APP substrate protein. Therefore, β-secretase is a primary target for anti-amyloid therapeutic drug design. Several approaches have been undertaken to find an effective inhibitor of human β-secretase activity, mostly in the field of peptidomimetic, non-cleavable substrate analogues. This review describes strategies targeting BACE mRNA recognition and its down-regulation based on the antisense action of small inhibitory nucleic acids (siNAs). These include antisense oligonucleotides, catalytic nucleic acids - ribozymes and deoxyribozymes - as well as small interfering RNAs (siRNAs). While antisense oligonucleotides were first used to identify an aspartyl protease with β-secretase activity, all the strategies now demonstrate that siNAs are able to inhibit BACE gene expression in a sequence-specific manner, measured both at the level of its mRNA and at the level of protein. Moreover, knock-down of BACE reduces the intra- and extracellular population of Aβ40 and Aβ42 peptides. An anti-amyloid effect of siNAs is observed in a wide spectrum of cell lines as well as in primary cortical neurons. Thus targeting BACE with small inhibitory nucleic acids may be beneficial for the treatment of Alzheimer's disease and for future drug design.

Keywords

EN

β-amyloid peptide; deoxyribozymes; small interfering RNAs; hammerhead ribozymes; Alzheimer's disease; β-secretase

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2004
• Volume: 51
• Issue: 2
• Pages: 431-444

Dates

published

2004

received

2004-05-03

accepted

2004-05-14

Contributors

author

Barbara Nawrot

• Centre of Molecular and Macromolecular Studies of Polish Academy of Sciences, Łódź, Poland

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