RNA interference in silencing of genes of Alzheimer's disease in cellular and rat brain models.
Accumulation of insoluble aggregates of beta-amyloid peptide, a cleavage product of amyloid precursor protein, is thought to be a central step in the pathogenesis of Alzheimer's disease. The major enzymes required for the generation of toxic amyloid-beta peptide are beta-(BACE1) and gamma-secretases. Here, we present the rational design and the application of synthetic and lentivirus vector-encoded siRNAs for specific and efficient knockdown of overexpressed and endogenous BACE1, both in dividing and neural stem cells and in a rat brain. We also tested an approach to anti-amyloid therapy by the use of the allele-specific siRNAs to silence the mutant presenilin 1 (L392V PS-1), the main component of gamma-secretase, responsible for development of Familial Alzheimer's disease. Reducing the level of beta-amyloid accumulation in the brain could be beneficial for metabolic studies as well as potential therapeutic approach for prevention and treatment of Alzheimer's disease.
Sierant
Malgorzata
M
Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland.
Kubiak
Katarzyna
K
Kazmierczak-Baranska
Julia
J
Paduszynska
Alina
A
Kuwabara
Tomoko
T
Warashina
Masaki
M
Nacmias
Benedetta
B
Sorbi
Sandro
S
Nawrot
Barbara
B
D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000628:therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000201:enzymology*; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006624:Hippocampus / Q000201:enzymology; D006801:Humans; D023421:Models, Animal; D010455:Peptides / Q000378:metabolism; D053764:Presenilin-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats
D016229:Amyloid beta-Peptides; D010455:Peptides; D053764:Presenilin-1; D034741:RNA, Small Interfering; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509281:Bace1 protein, rat