One characteristic neuropathological feature of Alzheimer's disease (AD) is profound neuronal loss in the nucleus basalis of Meynert, the major source of cholinergic innervation of the cerebral cortex. Clinically, anticholinergic activity causes a decline in cognitive function and increases the risk of dementia, thus possibly enhancing AD pathologies and neurodegeneration. Until now there has been insufficient human neuropathological data to support this conclusion. Experimental studies using a tauopathy mouse model demonstrated anticholinergics enhanced tau pathology and neurodegeneration corresponding to central anticholinergic activity. Additionally, donepezil, a cholinesterase inhibitor, ameliorated tau pathology and neurodegeneration in the same mouse model. These results indicate the balance between cholinergic and anticholinergic activities might affect neurodegeneration. Importantly, neurodegeneration observed in the mouse model seemed to correspond to the distribution of microglial activation, and it was reported that neuroinflammation plays an important role in the pathomechanism of AD, while anticholinergic activity augments inflammatory responses. Moreover, some studies indicated β-amyloid itself depletes cholinergic function similarly to anticholinergic activity. Thus, anticholinergic activity might initiate and/or accelerate AD pathology. Limited human data support the conclusion that anticholinergic activity enhances AD-related neuropathology and neurodegeneration. However, experimental data from a tauopathy mouse model indicated anticholinergic activity might enhance neurodegeneration with enhanced neuroinflammation including microglial activation.

Keywords:
Anticholinergic activity, Neuropathology, Alzheimerߣs disease, Tau pathology, Neuroinflammation
1.
Arendt T, Bigl V, Arendt A, Tennstedt A: Loss of neurons in the nucleus basalis of Meynert in Alzheimer's disease, paralysis agitans and Korsakoff's disease. Acta Neuropathol 1983;61:101-108.
2.
Francis PT, Palmer AM, Snape M, Wilcock GK: The cholinergic hypothesis of Alzheimer's disease: a review of progress. J Neurol Neurosurg Psychiatry 1999;66:137-147.
3.
Farlow MR: Do cholinesterase inhibitors slow progression of Alzheimer's disease? Int J Clin Pract Suppl 2002;127:37-44.
4.
Giacobini E: Do cholinesterase inhibitors have disease-modifying effects in Alzheimer's disease? CNS Drugs 2001;15:85-91.
5.
Giacobini E: Is anti-cholinesterase therapy of Alzheimer's disease delaying progression? Aging (Milano) 2001;13:247-254.
6.
Hashimoto M, Kazui H, Matsumoto K, Nakano Y, Yasuda M, et al: Does donepezil treatment slow the progression of hippocampal atrophy in patients with Alzheimer's disease? Am J Psychiatry 2005;162:676-682.
7.
Wagg A: The cognitive burden of anticholinergics in the elderly - implications for the treatment of overactive bladder. Eur Urol Rev 2012;7:42-49.
8.
Ancelin ML, Artero S, Portet F, Dupuy AM, Touchon J, et al: Non-degenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: longitudinal cohort study. BMJ 2006;332:455-459.
9.
Carriere I, Fourrier-Reglat A, Dartigues JF, Rouaud O, Pasquier F, et al: Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-City Study. Arch Intern Med 2009;169:1317-1324.
10.
Moore AR, O'Keeffe ST: Drug-induced cognitive impairment in the elderly. Drugs Aging 1999;15:15-28.
11.
Tune L, Carr S, Hoag E, Cooper T: Anticholinergic effects of drugs commonly prescribed for the elderly: potential means for assessing risk of delirium. Am J Psychiatry 1992;149:1393-1394.
12.
Mulsant BH, Pollock BG, Kirshner M, Shen C, Dodge H, et al: Serum anticholinergic activity in a community-based sample of older adults: relationship with cognitive performance. Arch Gen Psychiatry 2003;60:198-203.
13.
Hori K, Konishi K, Watanabe K, Uchida H, Tsuboi T, et al: Influence of anticholinergic activity in serum on clinical symptoms of Alzheimer's disease. Neuropsychobiology 2011;63:147-153.
14.
Fox C, Smith T, Maidment I, Chan WY, Bua N, et al: Effect of medications with anti-cholinergic properties on cognitive function, delirium, physical function and mortality: a systematic review. Age Ageing 2014;43:604-615.
15.
Perry EK, Kilford L, Lees AJ, Burn DJ, Perry RH: Increased Alzheimer pathology in Parkinson's disease related to antimuscarinic drugs. Ann Neurol 2003;54:235-238.
16.
Yoshiyama Y, Kojima A, Itoh K, Uchiyama T, Arai K: Anticholinergics boost the pathological process of neurodegeneration with increased inflammation in a tauopathy mouse model. Neurobiol Dis 2012;45:329-336.
17.
Yoshiyama Y, Kojima A, Ishikawa C, Arai K: Anti-inflammatory action of donepezil ameliorates tau pathology, synaptic loss, and neurodegeneration in a tauopathy mouse model. J Alzheimers Dis 2010;22:295-306.
18.
Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, et al: Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 2007;53:337-351.
19.
Jack CR Jr, Wiste HJ, Knopman DS, Vemuri P, Mielke MM, et al: Rates of beta-amyloid accumulation are independent of hippocampal neurodegeneration. Neurology 2014;82:1605-1612.
20.
Yoshiyama Y, Lee VM, Trojanowski JQ: Therapeutic strategies for tau mediated neurodegeneration. J Neurol Neurosurg Psychiatry 2013;84:784-795.
21.
Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, et al: Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 2009;11:909-913.
22.
Kobayashi F, Yageta Y, Yamazaki T, Wakabayashi E, Inoue M, et al: Pharmacological effects of imidafenacin (KRP-197/ONO-8025), a new bladder selective anti-cholinergic agent, in rats. Comparison of effects on urinary bladder capacity and contraction, salivary secretion and performance in the Morris water maze task. Arzneimittelforschung 2007;57:147-154.
23.
Oka T, Nakano K, Kirimoto T, Matsuura N: Effects of antimuscarinic drugs on both urinary frequency and cognitive impairment in conscious, nonrestrained rats. Jpn J Pharmacol 2001;87:27-33.
24.
Suzuki M, Noguchi Y, Okutsu H, Ohtake A, Sasamata M: Effect of antimuscarinic drugs used for overactive bladder on learning in a rat passive avoidance response test. Eur J Pharmacol 2007;557:154-158.
25.
Ishihara T, Hong M, Zhang B, Nakagawa Y, Lee MK, et al: Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 1999;24:751-762.
26.
Sahara N, Murayama M, Lee B, Park JM, Lagalwar S, et al: Active c-jun N-terminal kinase induces caspase cleavage of tau and additional phosphorylation by GSK-3beta is required for tau aggregation. Eur J Neurosci 2008;27:2897-2906.
27.
Pollak Y, Gilboa A, Ben-Menachem O, Ben-Hur T, Soreq H, et al: Acetylcholinesterase inhibitors reduce brain and blood interleukin-1beta production. Ann Neurol 2005;57:741-745.
28.
Tyagi E, Agrawal R, Nath C, Shukla R: Effect of anti-dementia drugs on LPS induced neuroinflammation in mice. Life Sci 2007;80:1977-1983.
29.
Satapathy SK, Ochani M, Dancho M, Hudson LK, Rosas-Ballina M, et al: Galantamine alleviates inflammation and other obesity-associated complications in high-fat diet-fed mice. Mol Med 2011;17:599-606.
30.
Jiang Y, Zou Y, Chen S, Zhu C, Wu A, et al: The anti-inflammatory effect of donepezil on experimental autoimmune encephalomyelitis in C57 BL/6 mice. Neuropharmacology 2013;73:415-424.
31.
Thomsen MS, Mikkelsen JD: The alpha7 nicotinic acetylcholine receptor ligands methyllycaconitine, NS6740 and GTS-21 reduce lipopolysaccharide-induced TNF-alpha release from microglia. J Neuroimmunol 2012;251:65-72.
32.
Pavlov VA, Tracey KJ: Controlling inflammation: the cholinergic anti-inflammatory pathway. Biochem Soc Trans 2006;34:1037-1040.
33.
Kolgazi M, Uslu U, Yuksel M, Velioglu-Ogunc A, Ercan F, et al: The role of cholinergic anti-inflammatory pathway in acetic acid-induced colonic inflammation in the rat. Chem Biol Interact 2013;205:72-80.
34.
Wang J, Zhang HY, Tang XC: Huperzine A improves chronic inflammation and cognitive decline in rats with cerebral hypoperfusion. J Neurosci Res 2010;88:807-815.
35.
Pavlov VA, Ochani M, Gallowitsch-Puerta M, Ochani K, Huston JM, et al: Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Proc Natl Acad Sci USA 2006;103:5219-5223.
36.
Pavlov VA, Parrish WR, Rosas-Ballina M, Ochani M, Puerta M, et al: Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway. Brain Behav Immun 2009;23:41-45.
37.
Oddo S, Caccamo A, Green KN, Liang K, Tran L, et al: Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease. Proc Natl Acad Sci USA 2005;102:3046-3051.
38.
Medeiros R, Castello NA, Cheng D, Kitazawa M, Baglietto-Vargas D, et al: Alpha7 nicotinic receptor agonist enhances cognition in aged 3xTg-AD mice with robust plaques and tangles. Am J Pathol 2014;184:520-529.
39.
Kar S, Slowikowski SP, Westaway D, Mount HT: Interactions between beta-amyloid and central cholinergic neurons: implications for Alzheimer's disease. J Psychiatry Neurosci 2004;29:427-441.
40.
Abe E, Casamenti F, Giovannelli L, Scali C, Pepeu G: Administration of amyloid beta-peptides into the medial septum of rats decreases acetylcholine release from hippocampus in vivo. Brain Res 1994;636:162-164.
41.
Blusztajn JK, Berse B: The cholinergic neuronal phenotype in Alzheimer's disease. Metab Brain Dis 2000;15:45-64.
42.
Harkany T, De Jong GI, Soos K, Penke B, Luiten PG, et al: Beta-amyloid (1-42) affects cholinergic but not parvalbumin-containing neurons in the septal complex of the rat. Brain Res 1995;698:270-274.
43.
Itoh A, Nitta A, Nadai M, Nishimura K, Hirose M, et al: Dysfunction of cholinergic and dopaminergic neuronal systems in beta-amyloid protein-infused rats. J Neurochem 1996;66:1113-1117.
44.
Giovannelli L, Casamenti F, Scali C, Bartolini L, Pepeu G: Differential effects of amyloid peptides beta-(1-40) and beta-(25-35) injections into the rat nucleus basalis. Neuroscience 1995;66:781-792.
45.
Watanabe T, Iwasaki K, Ishikane S, Naitou T, Yoshimitsu Y, et al: Spatial memory impairment without apoptosis induced by the combination of beta-amyloid oligomers and cerebral ischemia is related to decreased acetylcholine release in rats. J Pharmacol Sci 2008;106:84-91.
46.
Bellucci A, Luccarini I, Scali C, Prosperi C, Giovannini MG, et al: Cholinergic dysfunction, neuronal damage and axonal loss in TgCRND8 mice. Neurobiol Dis 2006;23:260-272.
47.
Hu L: The impact of Aβ-plaques on cortical cholinergic and non-cholinergic presynaptic boutons in Alzheimer's disease-like transgenic mice. Neuroscience 2003;121:421-432.
48.
Bales KR: Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-A antibody. J Clin Invest 2006;116:825-832.
49.
Wong TP, Debeir T, Duff K, Cuello AC: Reorganization of cholinergic terminals in the cerebral cortex and hippocampus in transgenic mice carrying mutated presenilin-1 and amyloid precursor protein transgenes. J Neurosci 1999;19:2706-2716.
50.
German DC, Yazdani U, Speciale SG, Pasbakhsh P, Games D, et al: Cholinergic neuropathology in a mouse model of Alzheimer's disease. J Comp Neurol 2003;462:371-381.
51.
Perez SE, Dar S, Ikonomovic MD, De Kosky ST, Mufson EJ: Cholinergic forebrain degeneration in the APPswe/PS1DeltaE9 transgenic mouse. Neurobiol Dis 2007;28:3-15.
52.
Ramos-Rodriguez JJ, Pacheco-Herrero M, Thyssen D, Murillo-Carretero MI, Berrocoso E, et al: Rapid beta-amyloid deposition and cognitive impairment after cholinergic denervation in APP/PS1 mice. J Neuropathol Exp Neurol 2013;72:272-285.
53.
Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, et al: Inflammation and Alzheimer's disease. Neurobiol Aging 2000;21:383-421.
54.
Serrano-Pozo A, Muzikansky A, Gomez-Isla T, Growdon JH, Betensky RA, et al: Differential relationships of reactive astrocytes and microglia to fibrillar amyloid deposits in Alzheimer disease. J Neuropathol Exp Neurol 2013;72:462-471.
55.
Serrano-Pozo A, Mielke ML, Gomez-Isla T, Betensky RA, Growdon JH, et al: Reactive glia not only associates with plaques but also parallels tangles in Alzheimer's disease. Am J Pathol 2011;179:1373-1384.
56.
Birch AM, Katsouri L, Sastre M: Modulation of inflammation in transgenic models of Alzheimer's disease. J Neuroinflamm 2014;11:25.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.