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Chapter 4

The Bimodal Features of Butyrylcholinesterase in Cholinergic Neurotransmission and Amyloid Suppression

While cholinesterase inhibitors are used to treat Alzheimer's disease- AD, the Amyloid beta Aβ cascade hypothesis leads to the development of anti-amyloid therapies. Disease-modifying intervention could involve decreasing Aβ production, intervening with Aβ aggregation and/or stimulating clearance of already formed Aβ fibrils. Recent findings suggest a protective role for butyrylcholinesterase, BChE from amyloid accumulation, suggesting its use as an AD-modifyer. In particular, this should be important for carriers of the Kalow BChE- K variant, which is a long-debated risk factor for AD with 20% incidence. The A539T substitution in BChE-K is located at the C-terminus, which is essential both for BChE tetramerization and for its capacity to attenuate Aβ fibril formation. We have recently found that BChE-K is inherently unstable compared to “usual” BChE-U, resulting in reduced hydrolytic activity and predicting prolonged acetylcholine maintenance and protection from AD for BChE-K carriers. Supporting this notion, BSP-K, a synthetic peptide derived from the C-terminus of BChE-K, displayed impaired inter-molecular interactions and was less potent in suppressing Aβ oligomerization than its BSP-U counterpart. Correspondingly, highly-purified recombinant human rBChE-U monomers suppressed β-amyloid fibril formation less effectively than dimers, which also protected cultured neuroblastoma cells from Aβ neurotoxicity. Structurally-derived changes due to the A539T substitution in BChE-K can hence account for both its neuroprotective characteristics caused by sustained acetylcholine levels, and for its causing an elevated AD risk due to inefficient interference with amyloidogenic processes. In this chapter, we discuss various anti-amyloid therapies and the structural basis for BChE involvement in aggregation of Aβ.

Publication details


Print publication date
07 May 2010
Copyright year
2010
Print ISBN
978-1-84973-063-1
PDF eISBN
978-1-84973-106-5
From the book series:
Drug Discovery