23 May 2011. Short of injecting reagents into the brains of AD patients, scientists in Ireland have produced what could be the best evidence to date that cellular prion protein (PrPc) mediates Aβ’s dirty work in neurons. In this week’s Journal of Neuroscience, Michael Rowan and colleagues at Trinity College Dublin report that blocking the Aβ-binding domain of PrPc keeps Aβ from disrupting synaptic plasticity. They show it by putting patient-derived Aβ into the brains of live rats.
“This provides a most convincing demonstration that PrPc is required for AD-related Aβ toxicity at synapses in vivo,” wrote Stephen Strittmatter of Yale University School of Medicine, New Haven, Connecticut, in an e-mail to ARF.
Strittmatter’s lab proposed the Aβ-PrPc connection several years ago (ARF related news story on Laurén et al., 2009), and others have since confirmed that Aβ oligomers bind PrPc with high affinity and specificity (ARF related news story on Balducci et al., 2010; Chen et al., 2010). However, other analyses have showed that Aβ can harm synapses in the absence of PrPc (Kessels et al., 2010; Calella et al., 2010), challenging the physiological importance of the Aβ-PrPc interaction.
As these investigations had used synthetic and transgenic mouse-derived Aβ with varying structures and biochemical properties, first author Andrew Barry and colleagues sought to clarify matters by testing the “real stuff.” Previously, the Rowan lab showed that Aβ from AD patients’ cerebrospinal fluid could block LTP, a measure of synaptic plasticity, in rat hippocampus in vivo (ARF related news story on Klyubin et al., 2008). For the current study, the researchers demonstrated LTP disruption by intracerebrovascular injection of soluble extracts from AD patient brain into the hippocampus of anesthetized rats. Importantly, they achieved the LTP effects with Aβ doses that did not affect other measures of synaptic function, such as baseline transmission.
Further experiments confirmed that Aβ and its interaction with PrPc are required for the LTP inhibition. Potentiation occurred just fine when antibodies were used to pre-clear Aβ from the injected AD brain material. Injections of antibody fragments specific for PrPc’s Aβ-binding region also normalized LTP in the rat hippocampus; antibody fragments recognizing a different PrPc region did not.
Is this study a be-all-end-all? “I would be surprised if there isn’t some lingering controversy,” Rowan wrote in an e-mail to ARF. In his view, other studies may have come to different conclusions because they tested non-physiological, high concentrations of Aβ, potentially bypassing the need for PrPc, Rowan suggested. A recent Nature Neuroscience editorial brings to light this problem of varying protocols and Aβ sources, and urges scientists to state precisely how they purified their Aβ species, and to define their structure and aggregation state as rigorously as possible.
Gianluigi Forloni, at the Mario Negri Institute for Pharmacological Research in Milan, Italy, believes a possible explanation for the discrepancies regarding Aβ’s LTP effects is that “β amyloid-PrPc binding is real, but its functional relevance is relative.” (See also Forloni and Balducci, 2011.) PrPc is one of many molecules that interact with β amyloid oligomers, but this association may hold meaning only under certain electrophysiological conditions, Forloni suggested in an e-mail to ARF. This issue may find clarity in soon-to-be-published and ongoing studies testing the therapeutic potential of anti-PrP antibodies, Rowan noted.—Esther Landhuis.
Barry AE, Klyubin I, Mc Donald JM, Mably AJ, Farrell MA, Scott M, Walsh DM, Rowan MJ. Alzheimer’s disease brain-derived amyloid-beta-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein. J. Neurosci. 18 May 2011;31(20):7259-7263. Abstract