A New Therapeutic Target in Alzheimer's Disease Treatment: Attention to Butyrylcholinesterase

Nigel H. Greig, Tada Utsuki, Qian-sheng Yu, Xiaoxiang Zhu, Harold W. Holloway, TracyAnn Perry, Bong Lee, Donald K. Ingram, Debomoy K. Lahiri; National Institute on Aging (NIA), Baltimore, MD; Indiana University School of Medicine, Indianapolis, IN.

Curr Med Res Opin. 2001;17(3) 

In This Article

Summary and Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the elderly, characterised by widespread loss of central cholinergic function. The only symptomatic treatment proven effective to date is the use of cholinesterase (ChE) inhibitors to augment surviving cholinergic activity. ChE inhibitors act on the enzymes that hydrolyse acetylcholine (ACh) following synaptic release. In the healthy brain, acetylcholinesterase (AChE) predominates (80%) and butyrylcholinesterase (BuChE) is considered to play a minor role in regulating brain ACh levels. In the AD brain, BuChE activity rises while AChE activity remains unchanged or declines. Therefore both enzymes are likely to have involvement in regulating ACh levels and represent legitimate therapeutic targets to ameliorate the cholinergic deficit. The two enzymes differ in location, substrate specificity and kinetics. Recent evidence suggests that BuChE may also have a role in the aetiology and progression of AD beyond regulation of synaptic ACh levels. Experimental evidence from the use of agents with enhanced selectivity for BuChE (cymserine, MF-8622) and ChE inhibitors such as rivastigmine, which have a dual inhibitory action on both AChE and BuChE, indicate potential therapeutic benefits of inhibiting both AChE and BuChE in AD and related dementias. The development of specific BuChE inhibitors and the continued use of ChE inhibitors with the ability to inhibit BuChE in addition to AChE should lead to improved clinical outcomes.

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease that is characterised symptomatically by progressive deterioration of activities of daily living (ADL), behavioural disturbances and cognitive loss. A widespread cholinergic deficit is accepted to underlie the symptomatology of AD. As cholinergic neurotransmission declines, AD is associated with substantial reductions in the activity of the enzyme responsible for acetylcholine (ACh) synthesis, choline acetyltransferase (ChAT) and a subsequent decline in levels of ACh in the brain. This loss of cholinergic activity in those areas of the brain responsible for higher mental functions at least partially accounts for the impairments in ADL, behaviour and cognition.

Accompanying neurodegenerative features of AD include pathological changes, such as loss of cholinergic neurones in areas of the brain associated with higher mental functioning, particularly the neocortex and hippocampus (Figure 1), deposition of insoluble neurotoxic ß-amyloid protein (Aß) in senile plaques and the formation of neurofibrillary tangles[1]. The only successful treatment approach to date that has resulted in significant symptomatic benefit has been cholinesterase (ChE) inhibition[2]. The ChE inhibitor approach is preferable to direct receptor agonist therapy, as ChE inhibitors amplify the natural pattern of ACh release, rather than tonically or globally stimulating ACh receptors. ChE inhibitors with brain specificity slow the inactivation of ACh after synaptic release, thereby prolonging central ACh activity.

Neuropathological changes characteristic of AD. A = normal brain, B = AD brain, C = amyloid plaque, D = neurofibrillary tangle. (Courtesy of George Grossberg, St Louis University, USA.)


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