18 April2008. Aβ oligomers made in test tubes or found in conditioned cell-culture medium can put a damper on synaptic plasticity. But what of the real McCoy? Is Aβ from the human AD brain just as potent? The question may seem trivial, but it has no answer yet. Aβ oligomers isolated from patients are only just beginning to be shown to share the same penchant for disrupting synaptic transmission (see ARF related SfN story). Now in the 16 April Journal of Neuroscience, researchers led by Michael Rowan at Trinity College, Dublin, Ireland, add to the evidence by showing that Aβ from human cerebrospinal fluid, as well, blocks hippocampal plasticity in vivo in rats. What’s more, that block can be prevented by passive immunization, lending credence to immunotherapy strategies for treating Alzheimer disease.
First author Igor Klyubin and colleagues injected CSF samples from older (>50) healthy adults and AD patients into rat lateral cerebral ventricle just before inducing long-term potentiation (LTP) of synaptic transmission. The researchers found that Aβ-containing CSF suppressed LTP, whereas CSF immunodepleted of Aβ had no effect. Interestingly, it appears that it is dimers of Aβ that inhibit LTP, because the authors found that CSF containing only monomers had no effect. Whether higher-order Aβ species, such as the Aβ*56 that robs transgenic mice of memory (see ARF related news story), might also block LTP is unclear, since the researchers failed to find anything bigger than dimers in the six CSF samples they tested. “It will be important to determine the relationship between these different Aβ species in human CSF and brain samples in future studies,” write the authors.
The finding confirms what some have long believed to be the case, namely, that human Aβ has a pathophysiological role in the brain. For that reason, many research labs and pharmaceutical companies have pursued both active and passive immunotherapy strategies for depleting Aβ in the brain (for a recent update on vaccines in the clinic, see ARF related Keystone news). Klyubin and colleagues add to the hope that such a strategy might work. They found that if they first systemically immunized the rats with an Aβ antibody, the animals were protected against LTP suppression. This protection was afforded rats treated with both human Aβ-containing CSF and rats treated with Aβ from conditioned cell-culture medium.
The work shows that human CSF Aβ can be detrimental to neurons and that passive immunization may be a viable strategy for controlling its toxic effects. Interestingly, the findings suggest that passive immunotherapy may work directly in brain rather than by mopping up Aβ in the periphery—the original peripheral sink mechanism—because the researchers found small amounts of antibody actually ended up in the CSF (about 60 ng/ml). Recent data from Eli Lilly’s Phase 1 passive immunotherapy trial also suggest that antibodies enter the brain (see ARF related news story).
Finally, the finding raises some interesting questions about Aβ in normal CSF. While reduced CSF Aβ is indicative of AD, possibly because the peptides are getting stuck in plaques in the brain, Klyubin and colleagues found Aβ dimers in the CSF of cognitively normal older adults who had normal CSF levels of Aβ (and normal levels of tau). These CSF samples also inhibited LTP. The authors write that it is unclear at this time why these dimer-containing CSF samples inhibit LTP, and they caution against using Aβ dimers as a diagnostic indicator. “Although the present study was not designed to determine diagnostic potential, the presence of synaptic plasticity-disrupting Aβ dimers in CSF samples taken from people who were categorized as cognitively normal and the absence of detectable levels of dimers in CSF from patients diagnosed with AD indicates [sic] that CSF dimer concentration is unlikely to be useful on its own as a marker for clinical AD,” they write.—Tom Fagan.
Klyubin I, Betts V, Welzel AT, Blenno K, Zetterberg H, Wallin A, Lemere CA, Cullen WK, Peng Y, Wisniewski T, Selkoe DJ, Anwyl R, Walsh DM, Rowan MJ. Amyloid beta protein dimer-containing human CSF disrupts synaptic plasticity: Prevention by systemic passive immunization. J. Neurosci. 2008 April 16;28:4231-4237. Abstract