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


  1. In an elegant series of studies, one mechanism through which Aβ oligomers may cause synaptic dysfunction may be disruption in phophatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2 ) metabolism. The authors show that oligomeric Aβ destabilizes and reduces PtdIns(4,5)P2 in a pathway that involves extracellular calcium and requires intact function of NMDA. PtdIns(4,5)P2 is consumed after exposure to Aβ oligomers through two pathways involving PLC and synaptojanin 1. Further, mice haplo-deficient for synaptojanin-1, a protein critically involved with synaptic vesicle cycling and a key PtdIns(4,5)P2 phosphatase, were protected from Aβ oligomer toxicity.

    As the authors indicate, the results of their study are very interesting in light of the overexpression of synaptojanin 1 in trisomy 21/Down syndrome (DS). Individuals with DS begin developing Aβ deposits in their early thirties (although there have been reports of individuals younger than this being affected), and full blown AD pathology in their forties (Mann and Esiri, 1989). Interestingly, the development of dementia in this cohort begins to rise when adults reach their fifties (Lai, 1989). If synaptojanin 1 is overexpressed in DS, it may be another contributing factor to the early age of onset of AD in DS.

    There may be another interesting aspect to the synaptojanin 1 story in DS. As would be predicted, synaptojanin 1 protein levels are higher in DS relative to age-matched controls both in adult and fetal brain (Arai et al., 2002; Cheon et al., 2003). Other genes on chromosome 21 may further exacerbate the interaction between Aβ oligomers and phosphoinositide-mediated synaptic dysfunction. Synaptojanin 1 is phosphorylated by Minibrain kinase/dual specificity tyrosine-phosphorylation regulated kinase 1A (Mnb/Dyrk1A), which is also on chromosome 21 and over-expressed in DS (Adayev et al., 2006). Further, synaptojanin 1 phosphorylation by MNB/Dyrk1A leads to a small but measurable increase in the hydrolysis of PI(4,5)P2 (Adayev et al., 2006). Interestingly, there is a 27 percent reduction in total phospholipids in DS brain (Murphy et al., 2000) including a 37 percent reduction in phosphatidylinositol in the frontal cortex, an area that is vulnerable to Aβ pathology.

    Although phosphorylation of synaptojanin 1 by MNB/Dryk1A may generate only a small enhancement of PI15ase activity (Adayev et al., 2006), combined with overexpression of APP and potential generation of Aβ oligomers this may substantially increase synaptic dysfunction and leave neurons particularly vulnerable to additional AD pathology. In combination, the work by Berman and colleagues provides intriguing new insights into the factors leading to AD pathogenesis in DS.


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News Citations

  1. Beyond γ-Secretase: FAD Mutations Affect Calcium Channel via Lipid Messenger
  2. Keystone Drug News: Phase 2 Anti-oligomer Sugar Alcohol—How Might It Work?
  3. Aβ Oligomers and NMDA Receptors—One Target, Two Toxicities

Paper Citations

  1. . Phosphoinositides in cell regulation and membrane dynamics. Nature. 2006 Oct 12;443(7112):651-7. PubMed.
  2. . Polyphosphoinositol lipids: under-PPInning synaptic function in health and disease. Dev Neurobiol. 2007 Aug;67(9):1232-47. PubMed.
  3. . Reduced phosphoinositide concentrations in anterior temporal cortex of Alzheimer-diseased brains. J Neurochem. 1987 Apr;48(4):1018-21. PubMed.

Further Reading

Primary Papers

  1. . Oligomeric amyloid-beta peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism. Nat Neurosci. 2008 May;11(5):547-54. PubMed.