Diamant S, Podoly E, Friedler A, Ligumsky H, Livnah O, Soreq H.
Butyrylcholinesterase attenuates amyloid fibril formation in vitro.
Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8628-33.
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Association Between Butyrylcholinesterase and Amyloid-β: Good or Bad?
It is now an established fact that plaques and tangles in the Alzheimer disease brain contain the cholinergic enzyme acetylcholinesterase (AChE) and the related enzyme butyrylcholinesterase (BuChE) (2,3). While the precise function of cholinesterases in the pathology of AD remains unknown, experiments by Inestrosa and colleagues (6) have established that AChE interacts with the amyloid-β (Aβ) component of plaques and facilitates Aβ fibril formation. This finding is significant because maturation of Aβ into β-pleated sheet fibrils has been shown to be associated with toxic effects on neurons. BuChE, however, was found to have no effect on the quantity of Aβ fibrils formed.
Now, in a series of elegant experiments described in this paper, Soreq and colleagues convincingly demonstrate that human BuChE associates with soluble but not fibrillar Aβ fractions and attenuates the rate and delays the onset of Aβ fibril formation in vitro. A synthetic peptide derived from the BuChE C-terminus had similar effects on Aβ, and it was shown through mutagenesis that an aromatic tryptophan residue in the C-terminus is responsible for the interaction between BuChE and Aβ. Therefore, it appears that human BuChE exerts the opposite effect on Aβ compared to AChE. It is thus concluded that human BuChE is likely to be protective in AD by interfering with the formation of toxic Aβ protofibrils and insoluble fibrils, and that synthetic compounds based on the C-terminal domain of human BuChE may hold therapeutic value for AD.
The above conclusions are plausible and consistent with the findings presented in this paper and with the established toxic effects of fibrillar Aβ (7). However, recent information regarding various conformations of Aβ suggests a second possible interpretation of the results. Because of the deposition of large, nonfibrillar Aβ aggregates in diffuse plaques, the accumulation of fibrillar Aβ in compact plaques and the toxicity exerted by fibrillar Aβ on neurons, it had been assumed that the process of fibril formation is the primary enabling force for Aβ pathology in AD. Recent work has abundantly demonstrated that in contrast to Aβ aggregates found in plaques, the initial aggregates of Aβ are soluble, accumulate in neurons, and are released into the extracellular space (8). These so-called soluble Aβ oligomers have been shown to exert profound toxic effects on neurons, to cause neuronal loss, and to interfere with neuronal function. Small soluble Aβ oligomers (tetramers) potently inhibit hippocampal long-term potentiation (10), a process required for memory formation, for example. Intraneuronal injection of soluble Aβ also leads to neuronal degeneration in vitro (11), while soluble intraneuronal Aβ accumulates in multivesicular bodies at synapses and is associated with morphologic and chemical synaptic abnormalities (1,9).
It has been suggested that plaques serve as sinks for soluble Aβ oligomers, reducing the available levels of this Aβ conformation and thereby its toxic effects. The association of BuChE with soluble but not fibrillar Aβ, as reported by Soreq and colleagues, appears to interfere with Aβ fibril formation, implying that less of the soluble form of Aβ is converted into the large insoluble aggregates deposited in plaques. This suggests that BuChE results in an increased pool of soluble Aβ oligomers. Therefore, given the toxic effects of soluble Aβ oligomers outlined above, BuChE would be expected to increase the toxicity of soluble Aβ oligomers on neurons. Since formation of soluble Aβ oligomers by neurons occurs prior to plaque formation, the potential increase in this Aβ conformation by BuChE and the consequent toxic effects caused would be among the earliest pathological events contributing to the first manifestations of dementia. On the other hand, reductions in Aβ fibrils caused by BuChE and the consequent toxicity of this conformation of Aβ would influence the late stages of the disease process. The study by Soreq and colleagues is very important because it supports the notion that the association between BuChE and Aβ has biological relevance, and that drugs targeting BuChE may have disease-modifying effects. However, whether the association between BuChE and Aβ is protective via attenuation of amyloid fibril formation or toxic by increasing the levels of Aβ oligomers is a question that can only be resolved following in vivo experiments.
In AD brains, BuChE is associated primarily with mature, compact plaques which are composed of fibrillar Aβ (5). In contrast, the in vitro findings by Soreq and colleagues indicate that BuChE is associated primarily with soluble but not fibrillar Aβ. As acknowledged by the authors, these facts “may imply that BuChE incorporates into Aβ fibrils at a late phase of their formation.” Thus, while the early association of BuChE with soluble Aβ retards the process of fibril formation, the role of the BuChE associated with Aβ fibrils in the AD brain is as yet unknown. That BuChE is likely to have multiple functions in relation to Aβ is also suggested by recent observations that highly specific BuChE inhibitors increase Aβ levels in vitro and in vivo (4).
Almeida CG, Tampellini D, Takahashi RH, Greengard P, Lin MT, Snyder EM, Gouras GK.
Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses.
Neurobiol Dis. 2005 Nov;20(2):187-98.
Darvesh S, Hopkins DA, Geula C.
Neurobiology of butyrylcholinesterase.
Nat Rev Neurosci. 2003 Feb;4(2):131-8.
Geula C, Mesulam MM.
Cholinesterases and the pathology of Alzheimer disease.
Alzheimer Dis Assoc Disord. 1995;9 Suppl 2:23-8.
Greig NH, Utsuki T, Ingram DK, Wang Y, Pepeu G, Scali C, Yu QS, Mamczarz J, Holloway HW, Giordano T, Chen D, Furukawa K, Sambamurti K, Brossi A, Lahiri DK.
Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer beta-amyloid peptide in rodent.
Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17213-8.
Guillozet AL, Smiley JF, Mash DC, Mesulam MM.
Butyrylcholinesterase in the life cycle of amyloid plaques.
Ann Neurol. 1997 Dec;42(6):909-18.
Inestrosa NC, Alvarez A, Pérez CA, Moreno RD, Vicente M, Linker C, Casanueva OI, Soto C, Garrido J.
Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer's fibrils: possible role of the peripheral site of the enzyme.
Neuron. 1996 Apr;16(4):881-91.
Lorenzo A, Yankner BA.
Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red.
Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12243-7.
Deciphering the genesis and fate of amyloid beta-protein yields novel therapies for Alzheimer disease.
J Clin Invest. 2002 Nov;110(10):1375-81.
Takahashi RH, Milner TA, Li F, Nam EE, Edgar MA, Yamaguchi H, Beal MF, Xu H, Greengard P, Gouras GK.
Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology.
Am J Pathol. 2002 Nov;161(5):1869-79.
Townsend M, Shankar GM, Mehta T, Walsh DM, Selkoe DJ.
Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers.
J Physiol. 2006 Apr 15;572(Pt 2):477-92.
Zhang Y, Mclaughlin R, Goodyer C, LeBlanc A.
Selective cytotoxicity of intracellular amyloid beta peptide1-42 through p53 and Bax in cultured primary human neurons.
J Cell Biol. 2002 Feb 4;156(3):519-29.
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