22 December 2004. A paper published online 19 December in Nature Neuroscience takes aim at two omnipresent issues in Alzheimer disease research: Which form(s) of β amyloid (Aβ) are toxic and do symptoms such as subtle cognitive deficits require antecedent neurodegeneration? Karen Hsiao Ashe and colleagues at the Minneapolis Veterans Affairs Medical Center in Minnesota, in collaboration with Dennis Selkoe's group at Harvard University, Cambridge, Massachusetts, find that nonfibrillar Aβ oligomers—but not monomers—injected directly into the cerebral ventricles of normal rats lead to acute, but transient cognitive deficits.
The authors stress that the Aβ used in this experiment was "natural." That is, it was produced by Chinese hamster ovary (CHO) cells expressing mutant Aβ from a human transgene, a system developed by coauthor Dominic Walsh of Harvard. Thus, the researchers knew that they were injecting just monomer, just low-n oligomers, or both, but not larger, or fibrillar, Aβ aggregates. First author Jim Cleary, of the University of Minnesota, and colleagues assessed the cognitive effects of these natural Aβs using a learning task designed to study subtle cognitive changes in response to psychoactive drugs; the alternating lever cyclic ratio (ALCR) test requires rats to press levers in certain sequences to get food rewards.
Injecting a combination of both monomer and low-n oligomer Aβ produced significant decrements (approximately 50 to 100 percent increases in different error types) on the ALCR test within hours. When they separated monomers from oligomers, the researchers found that the oligomers alone (with trimers the dominant species), but not the monomers, were able to produce the cognitive deficits. This agrees well with Walsh's findings that it is the oligomers, not monomers, in conditioned cell medium that disrupts synaptic function (see ARF related news story). The researchers considered the possibility that CSF degrades monomers, but not oligomers. However, an in vitro control experiment indicated that this is not the case.
Interestingly, the effects were transient as well as acute—there were no deficits on testing one or three days later. This contrasts with a number of earlier studies of Aβ introduced into the CSF, which found permanent and even progressive cognitive deficits, though these studies were not looking for any acute effects. One exception was a study that found acute memory deficits following hippocampal injection of Aβ (Sweeney et al., 1997). Cleary and colleagues note that the earlier work used mixtures of synthetic Aβ of different sizes, some of which was fibrillar. Also, the Aβ mixtures of earlier studies (with the exception of the Sweeney et al. acute study) were several orders of magnitude more concentrated than those used here. Indeed, the authors write that the conditioned medium from their cells has Aβ concentrations approximately the same as that detected in normal human CSF.
What about long-term effects? The researchers found no evidence that their Aβ injections, even when given once a week for four consecutive weeks, had lasting or progressive effects on test performance outside the short periods following administration. The authors suggest this means "that soluble amyloid-β oligomers can produce transient brain dysfunction in the absence of neurological damage. This is an important concept, because it may provide an explanation for the observation that subtle brain dysfunction can be detected in certain individuals who are genetically at risk for Alzheimer disease but remain neurologically stable for many years before the expected
onset of disease."—Hakon Heimer.
Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH. Natural oligomers of the amyloid-β protein specifically disrupt cognitive function. Nat Neurosci. 2004 Dec 19; [Epub ahead of print]. Abstract