RNA therapeutics directed to the non coding regions of APP mRNA, in vivo anti-amyloid efficacy of paroxetine, erythromycin, and N-acetyl cysteine.
Lead compounds directed to the 5' leader of the Amyloid Precursor Protein transcript (i.e., paroxetine (SSRI), N-acetyl cysteine (antioxidant), and erythromycin (macrolide antibiotic)) were employed in a pilot study to evaluate their anti-amyloid efficacy in the TgCRND8 transgenic mouse model for Alzheimer's Disease (AD). The relative levels of Abeta peptide were reduced after exposure of mice to paroxetine (N=5), NAC (N=7), and erythromycin (N=7) relative to matched placebo counterparts. Paroxetine limited the levels of APP holoprotein and total Abeta peptide levels (measurements of Abeta were performed at two separate sites by quantitative western blotting and ELISA assay). The paroxetine data provided proof-of-concept for our strategy for further screening the APP 5'UTR target to identify novel drugs that exhibit anti-amyloid efficacy in vivo. Erythromycin and azithromycin were macrolide antibiotics that markedly changed the cleavage of the APP C-Terminal Fragment (CTF) in SH-SY5Y cells. Erythromycin provided orally to TgCRND8 mice consistently (100%) reduced brain Abeta(1-42) levels. These data demonstrated a highly statistically significant anti-amyloid trend for paroxetine, NAC and erythromycin. The potential for conducting further studies with these compounds using larger cohorts of TgCRND8 mice is discussed, particularly since erythromycin has recently been exposed to mice for a further 6 months (N=6). It will be possible to employ the chemical structures of paroxetine and erythromycin as starting points for drug design and development for AD therapeutics.
Tucker
Stephanie
S
Neurochemistry Laboratory, Division of Psychiatric Neurosciences and Genetics and Aging Research Unit, Massachusetts General Hospital, Boston, MA 02114, USA. Jrogers@partners.org
Ahl
Michelle
M
Cho
Hyun-Hee
HH
Bandyopadhyay
Sanghamitra
S
Cuny
Gregory D
GD
Bush
Ashley I
AI
Goldstein
Lee E
LE
Westaway
David
D
Huang
Xudong
X
Rogers
Jack T
JT
D020121:5' Untranslated Regions / Q000187:drug effects / Q000235:genetics; D000111:Acetylcysteine / Q000494:pharmacology* / Q000627:therapeutic use; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational / Q000494:pharmacology* / Q000627:therapeutic use; D004917:Erythromycin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D017374:Paroxetine / Q000494:pharmacology* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D010865:Pilot Projects; D014176:Protein Biosynthesis / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000187:drug effects*
D020121:5' Untranslated Regions; D016564:Amyloid beta-Protein Precursor; D015507:Drugs, Investigational; D010446:Peptide Fragments; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D017374:Paroxetine; D004917:Erythromycin; D000111:Acetylcysteine