Acetylcholinesterase (AChE), best known for hydrolyzing the neurotransmitter acetylcholine, is also found in the amyloid plaques that plague the brains of Alzheimer's patients. What part this protein has in progression of AD is unclear, but papers in the September 16 Biochemistry and the October Journal of Neurochemistry suggest that any role it does have may be related to enzymatic rather than fibrillogenic activity.
In the Journal of Neurochemistry, currently available online, Nibaldo Inestrosa and colleagues at the Pontificia Universidad Católica de Chile in Santiago, report that AChE can induce neuronal loss and cognitive impairment in the hippocampus. When first author Marcelo Chacón and coworkers injected bovine AChE into the dorsal hippocampus of adult rats, it caused the death of about 50 percent of the neurons along the dentate gyrus near the injection site. Injection of denatured AChE had no such effect. The neuronal degradation was accompanied by increased expression of glial fibrillary protein, an astrocytic marker, indicating the activation of reactive astrocytes. These rats declined in their performance on the Morris water maze test, as well, taking significantly longer than control animals to find the submerged platform. For example, eight days after training, treated animals needed more than 30 seconds to escape the water, while sham-treated animals or those treated with denatured protein did so in less than 20 seconds. All animals swam at the same speed, indicating no loss of motor function in the AChE-treated group.
Why injected AChE should have such an effect on the hippocampus is unclear, but may be related to its degradation of acetylcholine. In this regard, it is worth noting that AChE inhibitors are the only drugs which seem to offer any specific benefit to Alzheimer's patients (see ARF related news story).
In the journal Biochemistry, David Vaux and colleagues from the University of Oxford, England, follow up on previous work which showed that a 14-amino-acid stretch of AChE, which has sequence homology to amyloid β, can form amyloid fibrils. In this latest work, first author Matthew Cottingham shows that the 40-amino-acid T-peptide domain of AChE, which contains the Aβ homologous sequence, exists in the full-length enzyme as an α-helical structure.
First, Cottingham used circular dichroism spectroscopy to show that only the 14-amino-acid peptide forms β-sheet-based fibrils. In contrast, the full-length T-peptide forms an α-helical conformation. To see which conformation exists in full-length protein isolated from human tissue samples, Cottingham raised monoclonal antibodies that react with specific secondary structures. Antibody 105A, which recognizes the β-sheet conformation, reacts poorly with human AChE expressed from HEK293 cells, whereas antibody 55C, raised against the α-helical T40, immunoprecipitates the protein.
Cottingham and colleagues point out that they have not tried to determine what conformation exists in human AChE in vivo, but note that the enzyme may contain or give rise to fragments containing the aberrant β-sheet structure.—Tom Fagan