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Elevated Butyrylcholinesterase and Acetylcholinesterase May Predict The Development of Type 2 Diabetes Mellitus and Alzheimer's Disease
Elevated Butyrylcholinesterase and Acetylcholinesterase May Predict The Development of Type 2 Diabetes Mellitus and Alzheimer's Disease
http://intl.elsevierhealth.com/journals/mehy
a
Department of Computer Sciences and Systems Engineering, Andhra University,
Visakhapatnam 530 003, India
b
Endocrine and Diabetes Centre, 15-12-16 Krishnanagar, Visakhapatnam 530 002, India
c
UND Life Sciences, 13800 Fairhill Road, #321, Shaker Heights, OH 44120, USA
Summary Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), and lipid
peroxides are elevated and concentrations of endothelial nitric oxide (eNO) decreased in type 2 diabetes mellitus and
Alzheimer’s disease. This suggests that both these diseases are low-grade systemic inflammatory conditions and are
closely associated with each other. Recent studies revealed that plasma and tissue concentrations of enzymes
butyrylcholinesterase and acetylcholinesterase are elevated in type 2 diabetes and Alzheimer’s disease. Acetylcholine
has anti-inflammatory actions. Hence, elevated butyrylcholinesterase and acetylcholinesterase concentrations will
lead to a decrease in the levels of acetylcholine that could trigger the onset of low-grade systemic inflammation seen
in type 2 diabetes and Alzheimer’s disease. In view of this, we propose that butyrylcholinesterase and acetylcho-
linesterase will not only serve as therapeutic targets but also may serve as markers to predict the development of type
2 diabetes mellitus and Alzheimer’s disease.
c 2007 Elsevier Ltd. All rights reserved.
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2007.03.032
Elevated butyrylcholinesterase and acetylcholinesterase 1273
References
Acetate
Choline [1] Das UN. Clinical laboratory tools to diagnose inflammation.
IL-6, TNF-α Adv Clin Chem 2006;41:189–229.
Nitric Oxide
[2] Das UN. Is metabolic syndrome X an inflammatory condi-
tion? Exp Biol Med 2002;227:989–97.
[3] Ford ES. The metabolic syndrome and C-reactive protein,
Neurotransmission Inflammation fibrinogen, and leukocyte count: findings from the Third
National Health and Nutrition Examination Survey. Athero-
sclerosis 2003;168:351–8.
[4] Mohan IK, Das UN. Oxidant stress, anti-oxidants and nitric
Alzheimer’s disease oxide in noninsulin dependent diabetes mellitus. Med Sci
Type 2 Diabetes mellitus Res 1997;25:55–7.
[5] Cacabelos R, Barquero M, Garcia P, Alvaez XA, Varela de
Figure 1 Scheme showing relationship between Seijas E. Cerebrospinal fluid interleukin-1 beta (IL-1 beta)
cholinesterases, inflammation, pro-inflammatory cyto- in Alzheimer’s disease and neurological disorders. Method
kines, and Alzheimer’s disease and type 2 diabetes Find Exp Clin Pharmacol 1991;13:455–8.
mellitus. [6] Fillit H, Ding WH, Buee L, Kalman J, Altstiel L, Lawlor B,
et al. Elevated circulating tumor necrosis factor levels in
Thus, increased plasma, CSF, and RBC concentra- Alzheimer’s disease. Neurosci Lett 1991;129:318–20.
[7] Flanders KC, Lippa CF, Smith TW, Pollen TW, Sporn MB.
tions of acetylcholinesterase and butyrylcholinest-
Altered expression of transforming growth factor-beta in
erase indirectly reflect reduced concentrations of Alzheimer’s disease. Neurology 1995;45:1561–9.
ACh that, in turn, will enhance local and systemic [8] Donnelly RJ, Friedhoff AJ, Beer B, Blume AJ, Vitek MP.
inflammatory events. These results imply that ace- Interleukin-1 stimulates the beta-amyloid precursor protein
tylcholinesterase and butyrylcholinesterase could promoter. Cell Mol Neurobiol 1990;10:485–95.
[9] Blume AJ, Vitek MP. Focusing on IL-1-promotion of beta-
serve as markers of low-grade systemic inflamma-
amyloid precursor protein synthesis as an early event in
tion (Fig. 1). Alzheimer’s disease. Neurobiol Aging 1989;10:406–8.
[10] Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha
modulation for treatment of Alzheimer’s disease: a 6-
month pilot study. MedGenMed 2006;8:25.
Conclusion [11] Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI,
Watkins LR, et al. Vagus nerve stimulation attenuates the
Although many studies showed enhanced plasma systemic inflammatory response to endotoxin. Nature
levels of CRP, IL-6, TNF-a, and lipid peroxides 2000;405:458–62.
and low levels of NO in the plasma of patients with [12] Das UN. Is metabolic syndrome X a disorder of the brain
with the initiation of low-grade systemic inflammatory
type 2 diabetes mellitus and Alzheimer’s disease
events during the perinatal period? J Nutr Biochem [in
[1–6], some studies did not confirm these observa- press].
tions [1]. This suggests that more reliable markers [13] Kaplay SS. Acetylcholinesterase and butyrylcholinesterase
of low-grade systemic inflammation need to be of developing human brain. Biol Neonate 1976;28:65–73.
identified. ACh has anti-inflammatory actions and [14] Geula C, Mesulam MM. Cholinesterases and the pathology of
Alzheimer disease. Alzheimer Dis Assoc Disord
is an important neurotransmitter. Hence, measure-
1995;9(Suppl. 2):23–8.
ment of the activities of acetylcholinesterase and [15] Taylor P. In: Hardman J, Limbird J, Molinoff P, Raddon R,
butyrylcholinesterase enzymes may mirror the con- Gilman A, editors. The pharmacological basis of therapeu-
centrations of ACh in the brain, especially in Alz- tics. New York: McGraw-Hill; 1996. p. 161–76.
heimer’s disease. The observation that activities [16] Li B, Stribley J, Ticu A, Xic W, Schopfer L, Hammond P,
et al. Abundant tissue butyrylcholinesterase and its possi-
of acetylcholinesterase and butyrylcholinesterase
ble function in the acetylcholinesterase knockout mouse.
are enhanced in the plasma and RBCs of patients J Neurochem 2000;75:1320–31.
with type 2 diabetes mellitus and Alzheimer’s dis- [17] Darvesh S, Hopkins D, Geula C. Neurobiology of butyrylch-
ease suggests that they could be used as markers olinesterase. Nat Rev Neurobiol 2003;4:131–8.
of low-grade systemic inflammation. Based on [18] Silver A. The biology of cholinesterases. New York:
Elsevier/Agricultural Reserach Council Institute; 1974. p.
these evidences, we propose that estimation of
426–47.
acetylcholinesterase and butyrylcholinesterase en- [19] Mesulam M, Guillozet A, Shaw P, Levey A, Daysen E,
zymes are useful to predict prognosis and response Lockridge O. Acetylcholinesterase knockouts establish
to treatment in type 2 diabetes and Alzheimer’s central cholinergic pathways and can use butyrylcholinest-
1276 Rao et al.
erase to hydrolyze acetylcholine. Neuroscience 2002;110: [26] Abbott CA, Mackness MI, Kumar S, Olukoga AO, Gordon C,
627–39. Arrol S, et al. Relationship between serum butyrylcholin-
[20] Perry E, Perry R, Blessed G, Tomlinson B. Changes in brain esterase activity, hypertriglyceridaemia and insulin
cholinesterases in senile dementia of Alzheimer type. sensitivity in diabetes mellitus. Clin Sci (Lond) 1993;85:
Neuropathol Appl Neurobiol 1978;4:273–7. 77–81.
[21] Arendt T, Bruckner M, Lange M, Bigl V. Changes in [27] Hashim Y, Shepherd D, Wiltshire S, Holman RR, Levy
acetylcholinesterase and butyrylcholinesterase in Alzhei- JC, Clark A, et al. Butyrylcholinesterase K variant on
mer’s disease resemble embryonic development – a study chromosome 3q is associated with Type II diabetes in
of molecular forms. Neurochem Int 1992;21:381–96. white Caucasian subjects. Diabetologia 2001;44:
[22] Giacobini E. Cholinesterases: new roles in brain function 2227–30.
and in Alzheimer’s disease. Int J Geriatr Psych [28] Alcantara VM, Chautard-Freire-Maia EA, Scartezini M, Cerci
2003;18(Suppl. 1):S1–5. MS, Braun-Prado K, Picheth G. Butyrylcholinesterase activ-
[23] Guillozet A, Smiley J, Mash D, Mesulam M. Butyrylcholin- ity and risk factors for coronary artery disease. Scand J Clin
esterase in the life cycle of amyloid plaques. Ann Neurol Lab Invest 2002;62:399–404.
1997;42:909–18. [29] Calderon-Margalit R, Adler B, Abramson JH, Gofin J,
[24] Greig NH, Utsuki T, Ingram DK, Wang Y, Pepeu G, Scali C, Kark JD. Butyrylcholinesterase activity, cardiovascular
et al. Selective butyrylcholinsterase inhibition elevates risk factors, and mortality in middle-aged and elderly
brain acetylcholine, augments learning and lowers Alzhei- men and women in Jerusalem. Clin Chem 2006;52:
mer’s b-amyloid peptide in rodent. Proc Natl Acad Sci USA 845–52.
2005;102:17213–8. [30] Sreedhar G, Thota H, Allam AR, Suresh babu C, Siva Prasad
[25] Godfrey DA, Matschinsky FM. Enzymes of the cholinergic A, Divakar Ch. Alzheimer’s disease and type 2 diabetes
system in islets of Langerhans. J Histochem Cytochem mellitus: the cholinesterase connection? Lipids Health Dis
1975;23:645–51. 2006;5:28.