The most important therapeutic effect of
cholinesterase inhibitors (ChEI) on approximately 50% of
Alzheimer's disease (AD) patients is to stabilize cognitive function at a steady level during a 1-year period of treatment as compared to placebo. Recent studies show that in a certain percentage (approximately 20%) of patients this cognitive stabilizing effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic and
cholinergic. In vitro and in vivo studies have consistently demonstrated a link between
cholinergic activation and APP metabolism. Lesions of
cholinergic nuclei cause a rapid increase in cortical APP and CSF. The effect of such lesions can be reversed by ChEI treatment. Reduction in
cholinergic neurotransmission--experimental or pathological, such as in AD--leads to amyloidogenic metabolism and contributes to the neuropathology and
cognitive dysfunction. To explain the long-term effect of ChEI, mechanisms based on
beta-amyloid metabolism are postulated. Recent data show that this mechanism may not necessarily be related to
cholinesterase inhibition. A second important aspect of brain
cholinesterase function is related to enzymatic differences. The brain of mammals contains two major forms of
cholinesterases:
acetylcholinesterase (AChE) and
butyrylcholinesterase (BuChE). The two forms differ genetically, structurally, and for their kinetics.
Butyrylcholine is not a physiological substrate in mammalian brain, which makes the function of BuChE of difficult interpretation. In human brain, BuChE is found in neurons and glial cells, as well as in
neuritic plaques and tangles in AD patients. Whereas, AChE activity decreases progressively in the brain of AD patients, BuChE activity shows some increase. To study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor and found that extracellular
acetylcholine increased 15-fold from 5 nM to 75 nM concentrations with little
cholinergic side effect in the animal. Based on these data and on clinical data showing a relation between cerebrospinal fluid (CSF) BuChE inhibition and cognitive function in AD patients, we postulated that two pools of
cholinesterases may be present in brain, the first mainly neuronal and AChE dependent and the second mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of ACh concentration in brain and can be separated with selective inhibitors. Within particular conditions, such as in mice nullizygote for AChE or in AD patients at advanced stages of the disease, BuChE may replace AChE in hydrolizing brain
acetylcholine.