11 April 2008. Perhaps no topic is hotter in Alzheimer disease molecular research today than the synaptic effects of amyloid-β (Aβ) oligomers. These toxic assemblies disrupt synaptic function, and are leading contenders for causing cognitive decline starting early in disease. Soluble oligomers alter synapses by modulating surface levels of AMPA and NMDA receptors, and changing calcium fluxes. A new report from Tae-Wan Kim and Gilbert Di Paolo from the Taub Institute at Columbia University in New York adds another dimension to oligomer action, implicating oligomer-induced changes in the phosphoinositide signaling pathway in inhibition of synaptic long-term potentiation (LTP).
The study, reported in the April 6 edition of Nature Neuroscience online, shows that treating cultured neurons with Aβ oligomers causes a loss of membrane phosphatidylinositol 4,5-bisphosphate (PIP2), a major lipid messenger controlling neuronal and synaptic physiology. Indeed, the synaptotoxic effects of Aβ on LTP were prevented by reducing the activity of the major PIP2 phosphatase and maintaining PIP2 levels. The results suggest that Aβ oligomers act, at least in part, by decreasing signaling through the PIP2 pathway, and open up a new target for protecting neurons from Aβ toxicity.
“PIP2 is central to many housekeeping processes in neurons,” first author Diego Berman told Alzforum. “Changes in the levels of PIP2 in response to oligomeric Aβ could explain many of the phenotypes that have been observed with oligomeric Aβ,” he said.
Through its regulation of ion channels, endocytosis, exocytosis, and other functions, PIP2 plays a major role in neuronal physiology (for review, see Di Paolo and De Camilli, 2006; Hammond and Schiavo, 2007). Previous work from the Kim and Di Paolo labs showed that presenilin mutations associated with inherited forms of Alzheimer disease caused a decrease in PIP2 and changes in the activity of calcium channels regulated by the lipid (see ARF related news story). These changes were associated with enhanced production of Aβ42.
In the new study, Berman and colleagues asked whether elevation of Aβ itself affected PIP2 levels, which were reported some time ago to be decreased in AD brain (Stokes and Hawthorn, 1987). When they exposed two-week-old primary cortical neurons from mice to a low concentration (200 nM) of soluble synthetic Aβ oligomers, or to cell-derived Aβ in culture, they saw a rapid decrease in PIP2 levels of about 40 percent, which persisted over days. The decrease was reversible when Aβ was removed, and was specific for PIP2 over phosphatidylinositol 4-phosphate.
The decrease in PIP2 depended on oligomers: monomeric or fibrillar Aβ failed to evoke it. In addition, the effect was blocked by simultaneous treatment with scyllo-inositol, which interferes with the ability of oligomers to inhibit LTP, and is now in human clinical trials as an anti-amyloid therapy (see ARF related news story). Loss of PIP2 in response to Aβ depended on calcium and resulted in part from breakdown of the lipid by phospholipase C, which cleaves the inositol head group to yield phosphoinositide and diacylglycerol. The decrease in PIP2 was partially reversed by NMDA receptor blockade, a treatment shown previously to inhibit Aβ toxicity (see ARF related news story).
If PIP2 deficiency is important in Aβ toxicity, then finding a way to elevate PIP2 might counter that harm, the authors reasoned. That idea was borne out by experiments with mice having reduced levels of the PIP2 phosphatase synaptojanin 1. Heterozygote knockouts of synaptojanin had half the levels of phosphatase and elevated levels of PIP2. Berman and colleagues found that neurons from those mice were resistant to PIP2 depletion by Aβ oligomers. Furthermore, they showed that Aβ was no longer able to inhibit long-term potentiation in hippocampal slices from synaptojanin-reduced mice.
The protective effect of synaptojanin reduction suggests a new therapeutic target for blocking Aβ toxicity, the authors conclude. Synaptojanin is the main PIP2 phosphatase in brain and controls levels of PIP2 in neurons. The protein has never been implicated in AD before, Berman told ARF. “It’s a brand-new target,” he said.—Pat McCaffrey.
Berman DE, Dall'armi C, Voronov SV, McIntire LB, Zhang H, Moore AZ, Staniszewski A, Arancio O, Kim TW, Di Paolo G. Oligomeric amyloid-beta peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism. Nat Neurosci. 2008 Apr 6; [Epub ahead of print]