Is BuChE Inhibition as Important As AChE Inhibition for Alzheimer's?

Summarized by Robert W. Griffith, MD
July 26, 2002 (Reviewed: July 16, 2004)

Introduction

Impairment of cholinergic function is of central importance in Alzheimer disease, especially as it affects the neurons of the neocortex and the hippocampus. These areas of the brain deal with learning, memory, behavior, and emotional responses.

It has been shown quite convincingly that cholinesterase inhibitor therapy produces significant improvements in cognitive function in patients with Alzheimer's. Agents acting by inhibiting degradation of acetylcholine that are used include donepezil, galantamine, and rivastigmine. The first two drugs are selective acetylcholine esterase (AChE) inhibitors, while rivastigmine inhibits both AChE and butyrylcholine esterase (BuChE). Dr Ballard from Newcastle, England, has reviewed the potential role of BuChE in Alzheimer's disease.

What is BuChE?

BuChE has a similar molecular structure to that of AChE, but it lacks an anionic site and some aromatic residues. Contact with either enzyme causes acetylcholine to be cleaved and its neurotransmitter action terminated. While AChE is selective for acetylcholine breakdown, BuChE degrades several other substrates, including some interactive peptides.

Cholinergic therapy for Alzheimer's disease initially concentrated on AChE inhibition, as this is the main enzyme involved in the breakdown of acetylcholine in the normal brain. However, it now seems that the role of BuChE in hydrolysing acetylcholine may be relevant for brains with degenerative changes.

As Alzheimer disease progresses, AChE activity decreases in some brain regions, while BuChE activity increases. This is probably due to a relative increase in the numbers of BuChE-positive neurons. The increase in BuChE activity is greater in the hippocampus and in the temporal lobe in patients with Alzheimer's disease.

Amyloid plaques

Deposits of amyloid material are seen many years before the occurrence of neuronal degeneration and dementia; this suggests that some plaques may be quite benign. Both AChE and BuChE are associated with amyloid and neurofibrillary tangles in the brains of elderly persons with, and without, relevant cognitive impairment. It's therefore important to know what factors may contribute to the transformation of 'benign amyloid' to one with pathogenic actions. BuChE is a candidate factor for this. Advanced amyloid plaques in Alzheimer brains have up to 87% BuChE reactivity, compared with 20% reactivity in early, benign deposits. The presence of BuChE distinguishes the neurotoxic plaques from those seen in normal aging. It is therefore possible that BuChE plays a role in transforming benign amyloid to the 'malignant' form associated with neuronal degeneration and clinical dementia.

Laboratory studies

Workers at the US National Institutes of Health (NIH) are developing specific BuChE inhibitors for possible therapy in Alzheimer's disease. They have been studied in learning models using elderly rats. Improvements in learning resulted with lower doses of BuChE-selective inhibitors than when AChE-selective inhibitors were used. It was noted that high doses of the BuChE-selective agents did not cause typical cholinergic toxicity in animals.

Clinical data

Rivastigmine is a potent dual inhibitor of AChE and BuChE. Eighteen Alzheimer patients given rivastigmine (1 to 6 mg bid) in an open-label study demonstrated rapid and sustained dose-dependent inhibition of AChE and BuChE levels in the cerebrospinal fluid (CSF). In a separate study, long-term administration of rivastigmine showed that this effect was maintained for at least 12 months.

Rivastigmine is effective both in patients with Alzheimer disease and in dementia with Lewy bodies. However, It is not known yet whether Lewy bodies are associated with BuChE rather than AChE.

The clinical benefits of rivastigmine in Alzheimer disease appear comparable to those of the other two major AChE inhibitors, and side-effects are similar for all 3 drugs. It will be necessary to compare rivastigmine and either donepezil or galantamine in a head-to-head study to see if there are indeed relevant differences in efficacy and adverse effects, and to determine whether these differences, if present, are due to the BuChE inhibition provided by rivastigmine.

Comment

Cholinesterase inhibitors are clearly beneficial in Alzheimer's disease, but the relevance of BuChE versus AChE has yet to be determined. Dr Ballard postulates that, as Alzheimer disease progresses, the regulation of acetylcholine is increasingly dependent on BuChE. In the early stages of the disease AChE inhibition is more important, but as the disease advances BuChE inhibition may become more relevant to reduce the cholinergic deficit. The future holds the promise of clinical studies with specific BuChE inhibitors, which should clarify the relative roles of the two enzymes, and also contribute to progress in treating this disease.

Source

• Advances in the treatment of Alzheimer's disease: benefits of dual cholinesterase inhibition. CG. Ballard, Eur Neurol , 2002, vol. 47, pp. 64--70

Related Links
Cholinesterase Inhibitors for Alzheimer Disease
Effectiveness of Rivastigmine in Lewy-body Dementia
The cholinergic hypothesis of Alzheimer's disease: a review of progress

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