APP proteiinin syntetisoitumisesta

View Full Article (HTML) Get PDF (2057K) Regulation of APP Synthesis and Secretion by Neuroimmunophilin Ligands and Cyclooxygenase Inhibitors

1. ROBERT K.K. LEE^1,*,
2. RICHARD J. WURTMAN²

Article first published online: 25 JAN 2006

DOI: 10.1111/j.1749-6632.2000.tb06934.x

Abstract: We and others previously showed that both the synthesis of the amyloid precursor protein (APP) and its processing (i.e., to amyloidogenic Aβ peptides; soluble nonamyloidogenic APPs; and other APP fragments) are regulated by neurotransmitters.

• NA-systeemi ja eikosanoidikaskadi
  

Transmitters that elevate cellular cAMP levels (like norepinephrine and prostaglandins, which act on β-adrenergic receptors and prostaglandin E₂ receptors respectively) enhance APP synthesis and the formation of amyloidogenic APP holoprotein.

• PI-systeemi, AK-systeemi. 5HT-systeemi, Glu-systeemi ja niiden stimulaatio:
  

Transmitters that stimulate phosphatidylinositol hydrolysis (by activating muscarinic m1 or m3 receptors, serotoninergic 5HT2a or 5HT2c receptors, or metabotropic glutamate receptors of subtypes 1 or 5) increase the conversion of APP to soluble APPs, and decrease the formation of Aβ.

These findings suggest that drugs that regulate the activity of neurotransmitter receptors might be useful in preventing the excessive formation of Aβ or other amyloid precursors in Alzheimer's disease.

• We now show that neuroimmunophilin ligands (like cyclosporin A or FK-506) and nonsteroidal antiinflammatory agents (NSAIDs), including cyclooxygenase (COX)-2 inhibitors, can also prevent APP overexpression and the overproduction of amyloidogenic peptides. We observe that the enhancement of APP over-expression by prostaglandin E₂ is inhibited by neuroimmunophilin ligands like cyclosporin A or FK-506 (tacrolimus). We also find that the NSAIDs, which reduce prostaglandin synthesis by inhibiting COX-1 and -2 enzymes, might also be expected to lower APP levels. Our present data confirm that these drugs, as well as drugs that selectively inhibit COX-2, reduce the levels of amyloidogenic APP holoprotein in cultured neurons or in cultured astrocytes. We previously showed that elevations in cAMP, perhaps generated in response to prostaglandins, can suppress APPs secretion.
  
• The NSAIDs and COX inhibitors also increased levels of soluble APPs in the media of cultured astrocytes and neurons, perhaps acting by inhibition of prostaglandin production. Since APP holoprotein can be amyloidogenic, while APPs may be neurotrophic, our findings suggest that some neuroimmunophilin ligands, NSAIDs and COX-2 inhibitors might suppress amyloid formation and enhance neuronal regeneration in Alzheimer's disease.

KOMMENTTINI:
Tästä siltaa anandamidijärjestelmään( endokannabinoidijärjestelmään)
Siinä oleva tasapaino anandamidisignaloinnin jälkeen vapautuvan arakidonihapon ja muiden rasvahappojen ( eikosanoideja vaimentavien rasvahappojen) välillä vaikuttaa jatkossa eikosanoidikaskadiin, josta tulee APP-synteesin stimulaattorivaikutusta ja täten APP:n määrä tulee isommaksi jos eikosanoidikaskadi triggeröityy päälle. Koska se on samalla inflammatorinen, niin NSAID toimiiv vaikuttajana kahdessa taqsossa: APP:n määrän rajoittajana ja toisaalta edistämässä liukoisen , edullisen, sAPP muodon syntetisoimista, siitähän ei ole haittaa.

Miten nämä järjestelmät sAPP kierto ja anandamidimetabolia paikallisesti neuronissa suhtautuvat toiseensa? Tästä pitää katsoa jokin kuva tai tehdä kuva. ( 3.5. 2011).