| Popis: |
Selective muscarinic agonists that are directed at the ml muscarinic acetylcholine receptor (Ml mAChR) have been suggested as a rational treatment of Alzheimer’s disease (AD) (Fisher and Barak, 1995). Such muscarinic receptor agonists may activate a variety of transduction pathways, some of which are beneficial while others may be deleterious to AD. For example, activation of Ml mAChR increases phosphoinositide (PI) hydrolysis, arachidonic acid release, elevates intracellular calcium, increases the nonamyloidogenic processing of beta-amyloid precursor protein (APP), mediates tau dephosphorylation, induces formation of neurites and increases adenylate cyclase (AC) activity (Fisher and Barak, 1995; Haring et al., 1995; Heldman et al., 1996; Pittel et al., 1996). While most of these biochemical responses are considered to be beneficial for alleviating AD pathology, activation of AC may be deleterious, since mRNA of Gs, that mediates activation of AC, is elevated in AD brain (Harrison et al., 1991). Several muscarinic agonists that were synthesized in our laboratory activate preferentially distinct transduction pathways that lead to desirable effects, without affecting significantly AC activity (Fisher and Barak, 1995; Gurwitz et al., 1994). This chapter describes studies aimed at elucidating the mechanism which dictate the selectivity of these agonists. In addition, this chapter reports results of studies designed to identify transduction pathways that mediate the non-amyloidogenic APP processing induced by ml agonists (Fisher, 1997). |
