Abstract
In Alzheimer’s disease (AD), premature demise of acetylcholine-producing neurons and the consequent decline of cholinergic transmission associate with the prominent cognitive impairments of affected individuals. However, the enzymatic activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are altered rather late in the disease progress. This raised questions regarding the causal involvement of AChE and BChE in AD. Importantly, single nucleotide polymorphisms (SNPs), alternative splicing, and alternate promoter usage generate complex expression of combinatorial cholinesterase (ChE) variants, which called for testing the roles of specific variants in AD pathogenesis. We found accelerated amyloid fibril formation in engineered mice with enforced over-expression of the AChE-S splice variant which includes a helical C-terminus. In contrast, the AChE-R variant, which includes a naturally unfolded C-terminus, attenuated the oligomerization of amyloid fibrils and reduced amyloid plaque formation and toxicity. An extended N-terminus generated by an upstream promoter enhanced the damage caused by N-AChE-S, which in cell cultures induced caspases and GSK3 activation, tau hyperphosphorylation, and apoptosis. In the post-mortem AD brain, we found reduced levels of the neuroprotective AChE-R and increased levels of the neurotoxic N-AChE-S, suggesting bimodal contribution to AD progress. Finally, local unwinding of the α-helical C-terminal BChE peptide and loss of function of the pivotal tryptophan at its position 541 impair amyloid fibril attenuation by the common BChE-K variant carrying the A539T substitution, in vitro. Together, our results point to causal yet diverse involvement of the different ChEs in the early stages of AD pathogenesis. Harnessing the neuroprotective variants while reducing the levels of damaging ones may hence underlie the development of novel therapeutics.
Highlights
In Alzheimer’s disease (AD), premature demise of acetylcholine-producing neurons and the consequent decline of cholinergic transmission associate with the prominent cognitive impairments of affected individuals
The currently used cholinesterase inhibitor therapies mainly offer palliative relief, and a thorough understanding of the early stages of the disease is needed for successful future interventions. Both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are localized in amyloid plaques, and early reports showed that AChE is capable of facilitating Aβ fibril formation.[4]
For these reasons the in-vivo effect of AChE-S and AChE-R was examined in the APPsw mouse model, carrying the amyloid precursor protein (APP) with the “Swedish” mutation leading to early-onset Alzheimer’s disease
Summary
In Alzheimer’s disease (AD), premature demise of acetylcholine-producing neurons and the consequent decline of cholinergic transmission associate with the prominent cognitive impairments of affected individuals.
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