![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received for publication April 15, 2003.
Revised April 30, 2003.
Accepted for publication May 23, 2003.
The cholinergic hypothesis was initially presented over 20 years ago and suggests that a dysfunction of acetylcholine containing neurons in the brain contributes substantially to the cognitive decline observed in those with advanced age and Alzheimer's Disease (AD). This premise has since served as the basis for the majority of treatment strategies and drug development approaches for AD to date. Recent studies of the brains of patients who had mild cognitive impairment or early stage AD in which choline acetyltransferase (ChAT) and/or acetylcholinesterase (AChE) activity was unaffected (or even up-regulated) have, however, led some to challenge the validity of the hypothesis as well as the rationale for using cholinomimetics to treat the disorder, particularly in the earlier stages. These challenges, primarily based on assays of post mortem enzyme activity should be taken in perspective and evaluated within the wide range of cholinergic abnormalities known to exist in both aging and AD. The results of both postmortem and antemortem studies in aged humans and AD patients, as well as animal experiments suggest that a host of cholinergic abnormalities including alterations in choline transport, acetylcholine release, nicotinic and muscarinic receptor expression, neurotrophin support, and perhaps axonal transport may all contribute to cognitive abnormalities in aging and AD. Cholinergic abnormalities may also contribute to non-cognitive behavioral abnormalities as well as the deposition of toxic neuritic plaques in AD. Therefore, cholinergic-based strategies will likely remain valid as one approach to rational drug development for the treatment of AD other forms of dementia.
Key words:
Alzheimer's Disease, acetylcholine, cognition, dementia, memory, treatment
This article has been cited by other articles:
|
|
 |
|
  H. Salah-Uddin, D. R. Thomas, C. H. Davies, J. J. Hagan, M. D. Wood, J. M. Watson, and R. A. J. Challiss Pharmacological Assessment of M1 Muscarinic Acetylcholine Receptor-Gq/11 Protein Coupling in Membranes Prepared from Postmortem Human Brain Tissue J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 869 - 874. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. T. Blaszczyk and M. Mathys Treatment of Cognitive Decline and Psychiatric Disturbances Associated With Alzheimer's Dementia Journal of Pharmacy Practice, February 1, 2007; 20(1): 13 - 28. [Abstract] [PDF]
|
|
|
|
 |
|
 F. Chiappelli, A. M. Navarro, D. R. Moradi, E. Manfrini, and P. Prolo Evidence-Based Research in Complementary and Alternative Medicine III: Treatment of Patients with Alzheimer's Disease Evid. Based Complement. Altern. Med., December 1, 2006; 3(4): 411 - 424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Tabet Acetylcholinesterase inhibitors for Alzheimer's disease: anti-inflammatories in acetylcholine clothing! Age Ageing, July 1, 2006; 35(4): 336 - 338. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Geerts and G. T. Grossberg Pharmacology of Acetylcholinesterase Inhibitors and N-methyl-D-aspartate Receptors for Combination Therapy in the Treatment of Alzheimer's Disease J. Clin. Pharmacol., July 1, 2006; 46(suppl_1): 8S - 16S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Lewis, L. Hunihan, D. Franco, B. Robertson, J. Palmer, D. R. St. Laurent, B. N. Balasubramanian, Y. Li, and R. S. Westphal Identification and Characterization of Compounds That Potentiate NT-3-Mediated Trk Receptor Activity Mol. Pharmacol., April 1, 2006; 69(4): 1396 - 1404. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Freo, E. Ricciardi, P. Pietrini, M. B. Schapiro, S. I. Rapoport, and M. L. Furey Pharmacological Modulation of Prefrontal Cortical Activity During a Working Memory Task in Young and Older Humans: A PET Study With Physostigmine Am J Psychiatry, November 1, 2005; 162(11): 2061 - 2070. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Robinson Galanin and Cognition Behav Cogn Neurosci Rev, December 1, 2004; 3(4): 222 - 242. [Abstract] [PDF]
|
|
|
|
 |
|
 K. A. Sacco, K. L. Bannon, and T. P. George Nicotinic receptor mechanisms and cognition in normal states and neuropsychiatric disorders J Psychopharmacol, December 1, 2004; 18(4): 457 - 474. [Abstract] [PDF]
|
|
|
|
|
|
M. J. Millan, A. Gobert, S. Roux, R. Porsolt, A. Meneses, M. Carli, B. Di Cara, R. Jaffard, J.-M. Rivet, P. Lestage, et al. The Serotonin1A Receptor Partial Agonist S15535 [4-(Benzodioxan-5-yl)1-(indan-2-yl)piperazine] Enhances Cholinergic Transmission and Cognitive Function in Rodents: A Combined Neurochemical and Behavioral Analysis J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 190 - 203. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Fayuk and J. L. Yakel Regulation of Nicotinic Acetylcholine Receptor Channel Function by Acetylcholinesterase Inhibitors in Rat Hippocampal CA1 Interneurons Mol. Pharmacol., September 1, 2004; 66(3): 658 - 666. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-A. Barde Death of injured neurons caused by the precursor of nerve growth factor PNAS, April 20, 2004; 101(16): 5703 - 5704. [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
