Altered levels and splicing of the amyloid precursor protein in the adult rat hippocampus after treatment with DMSO or retinoic acid.
Alzheimer's disease and cognitive impairment in rats has been associated with an increase in the percentage of amyloid precursor protein (APP) containing the KPI domain. It has recently been reported that retinoic acid (RA) is capable of increasing the levels and altering the splicing ratio of APP in cultured SH-SY5Y cells. The effects of peripherally administered RA (64 or 640 micrograms/kg; i.p.; q.d.) on the abundance of APP, the ratio of the three major isoforms, and the relative abundance of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) were determined by rtPCR in the hippocampus of aged rats. Corresponding changes in choline acetyltransferase (ChAT) activity were also measured. Vehicle (DMSO) treated rats exhibited a 2 x (P < 0.01) increase in total APP and an 8 x (P < 0.001) decrease in the cyclophilin transcript. In addition, DMSO increased the percentage of APP 695 from 89% in saline treated rats to 94%. Treatment of RA in DMSO decreased the accumulation of total APP relative to cyclophilin at both the low (6.4 x; P < 0.01) and high (8 x; P < 0.05) dosages when compared to DMSO treated rats. Furthermore, the level of APP-695 decreased to 82% with low dosage of RA and 75% at high dosage of the total APP transcripts. No significant change in either NGF, NT-3, or BDNF transcripts were observed following low or high dosage RA administration relative to cyclophilin RNA nor was a change in ChAT activity detected at either of the dosages tested.(ABSTRACT TRUNCATED AT 250 WORDS)
Pan
J B
JB
Abbott Laboratories, Abbott Park, IL 60064-3500.
Monteggia
L M
LM
Giordano
T
T
D017398:Alternative Splicing / Q000187:drug effects*; D000591:Amino Acid Isomerases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003524:Cyclosporins / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D019696:Peptidylprolyl Isomerase; D016133:Polymerase Chain Reaction / Q000379:methods; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D014212:Tretinoin / Q000494:pharmacology*
D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D003524:Cyclosporins; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D014212:Tretinoin; D012313:RNA; D002795:Choline O-Acetyltransferase; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase; D004121:Dimethyl Sulfoxide