Abraham Fisher*
IsraelﾊInstitute for Biological Research, P.O.Box 19, 74100 Ness-Ziona,
Israel
*Corresponding author.ﾊﾊFAX:+972-8-9381-615
E-mail: fisher_
Abstract: The cholinergic hypofunction in Alzheimer's disease (AD)
appears to be linked with two other major hallmarks of this disease, b-amyloid
and hyperphosphorylated tau protein. Formation of b-amyloids
might impair the coupling of M1 muscarinic acetylcholine receptors (mAChR)
with G-proteins. This can lead to decreased signal transduction, a decrease
of trophic and non-amyloidogenic amyloid precursor protein (APPs) and generation
of more b-amyloids, aggravating further the cholinergic
deficiency. This review is an attempt to explore the M1 mAChR regulation
of b-amyloid metabolism, tau hyperphosphorylation
and cognitive functions. The therapeutic potential of M1-selective muscarinic
agonists including AF102B, AF150(S), AF267B (the AF series) is evaluated
and compared, when possible, with several FDA-approved acetylcholinesterase
inhibitors. These M1 agonists can elevate APPs, decrease tau protein
phosphorylation/hyperphosphorylation in vitro and in vivo and restore cognitive
impairments in several animal models for AD. Except for the M1 agonists,
no other compounds were reported yet with combined effects; e.g., amelioration
of cognition dysfunction and beneficial modulation of APPs/b-amyloid
together with tau hyperphosphorylation/phosphorylation. This property
of M1 agonists to alter different aspects associated with AD pathogenesis
could represent the most remarkable clinical value of such drugs.
Keywords: Alzheimer's disease, M1 muscarinic agonist, Animal model, b-Amyloid,
Tau
Copyrightｩ The Japanese Pharmacological Society 2000
[Back to TOC]