Novel therapeutic avenues in Alzheimer's disease based on m1 muscarinic agonists - An unifying concept

A. Fisher, R. Haring, Z. Pittel, R. Brandeis, N. Esshar, Y. Karton, H. Meshulam, P. Lazarovici, M. Kushnir, E. Heldman

Research output: Contribution to journalArticlepeer-review

Abstract

M1 selective muscarinic agonists may be effective in the treatment of Alzheimer's disease (AD). In the present paper we overviewed a number of recently reported findings regarding m1 agonists with particular emphasis on the AF series (eg project drugs AF102B, AF150(S)) and their relevance in a novel therapeutic strategy in this disease. These include among other properties, effects of muscarinic agonists on processing of amyloid precursor protein and neurite outgrowth. We also attempted to elucidate how m1 muscarinic-mediated neurite outgrowth can be affected by neurotrophines, kinase inhibitors like K252a and enhanced levels of secreted amyloid precursor protein (APPs). We used PC12 cells transfected with cDNA encoding the m1 muscarinic acetylcholine receptors (PC12M1 cells) for these studies. In these cells, nerve growth factor (NGF), basic fibroblast growth factor (bFGF) and muscarinic agonists induce neurotrophic effects which are expressed in neurite outgrowth. Treatment of PC12M1 cells with AF102B, in combination with either NGF or bFGF results in synergistic neurite outgrowth. Treatment of the cells with a combination of NGF and bFGF also resulted in an enhanced neurotrophic effect. K252a blocks NGF-induced neurite outgrowth without affecting bFGF-induced neurite outgrowth, yet enhances AF102B- induced neurite outgrowth. In addition, K252a does not affect the synergy between bFGF and AF102B, but inhibits the synergy between AF102B and NGF. The 9-carboxylic acid analog of K252a, K252b, which is impermeable through the cell membrane, does not alter any of these neurotrophic effects indicating the alkaloid K252a affects intracellular cascades. Addition of the 22C11 antibody, directed against the N-terminal of APPs, did not alter the combined neurotrophic response induced by NGF and the tested muscarinic agonists, indicating that secreted APPs do not play a major role in the mechanism that underlies this neurotrophic response. These results suggest that NGF, bFGF and muscarinic agonists induce neurite outgrowth via distinct intracellular pathways which interact at a convergence point, which is apparently not dependent on APPs. This indicates that m1 agonists may compensate for possible dysfunctions of neurotrophines in AD. Furthermore these results can be tied together with other previously reported beneficial effects of m1 agonists on β-amyloids, tau proteins and on mnemonic processes in various animal models for AD. Due to the positive role of m1 agonists on some of the identified 'villains' and risk factors in AD, such compounds may represent an unique therapeutic strategy in AD.

Original languageEnglish
Pages (from-to)150-157
Number of pages8
JournalInternational Journal of Geriatric Psychopharmacology
Volume1
Issue number3
StatePublished - 1 Dec 1998
Externally publishedYes

Keywords

  • AF series
  • Amyloid precursor protein
  • Basic fibroblast growth factor
  • K252a
  • M1 agonists
  • Muscarinic acetylcholine receptor
  • Nerve growth factor
  • Neurite outgrowth
  • Neurotrophic effect
  • PC12, PC12M1 cells

ASJC Scopus subject areas

  • Neuropsychology and Physiological Psychology
  • Pharmacology, Toxicology and Pharmaceutics (all)
  • Geriatrics and Gerontology
  • Pharmacology (medical)

Fingerprint

Dive into the research topics of 'Novel therapeutic avenues in Alzheimer's disease based on m1 muscarinic agonists - An unifying concept'. Together they form a unique fingerprint.

Cite this