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Amyloid-β peptide (Aβ) oligomers are likely to underlie the earliest amnesic changes in Alzheimer’s disease through impairment of synaptic function. A recent work from the laboratories of Tae-Wan Kim and Gilbert Di Paolo and colleagues implicates the phosphoinositide signaling pathway in synaptic changes due to elevation of Aβ oligomers. Given that phosphatidylinositol 4,5-bisphosphate (PIP2) is central to many essential processes in neurons including neuronal and synaptic function, reduction in the levels of PIP2 in response to oligomeric Aβ could explain many of the phenotypes that have been observed with oligomeric Aβ. The data open up a new target for protecting neurons from Aβ-induced synaptic impairment.
Synaptic changes are thought to underlie the earliest amnesic changes in Alzheimer’s disease (AD). A current view on the cause of these synaptic changes is that amyloid-β (Aβ) peptide oligomers are likely to cause them. The oligomers alter synapses by affecting the function of numerous proteins including receptors that are directly involved in excitatory neurotransmission such as AMPA and NMDA receptors, and probably by changing calcium flux through the membrane. A recent report in Nature Neuroscience titled ‘Oligomeric amyloid-Beta peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism’ (Nature Neuroscience 11, 547 – 554, 2008) from the laboratories of 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 occurring during inhibition of long-term potentiation (LTP), a type of synaptic plasticity that is thought to underlie learning and memory.
Phosphatidylinositol 4,5-bisphosphate (PIP2) is a major lipid messenger controlling many cellular processes including neuronal and synaptic function. Indeed, PIP2 plays an important regulatory role in neuronal physiology through the regulation of ion channels, endocytosis, exocytosis, and other cellular functions such as the cytoskeleton, nuclear events and the permeability and transport functions of membranes . Previous work from the Kim and Di Paolo laboratories showed that presenilin mutations linked to familial AD cause an imbalance in PIP2 metabolism . They also found that the transient receptor potential melastatin 7 (TRPM7)-associated Mg2+ -inhibited cation (MIC) channel was responsible for ion channel dysfunction, and the observed channel deficits were restored by the addition of PIP2, which is known to regulate the MIC/TRPM7 channel. These changes were associated with enhanced production of Aβ42. These observations together with the finding that PIP2 levels are decreased in AD brain , lead Berman et al. to ask whether elevation of Aβ42 affects levels of PIP2. When the authors exposed two-week-old primary cortical neurons from mice to soluble synthetic Aβ42 oligomers, or to cell-derived Aβ42 in culture, at a concentration of 200 nM that is known to produce synaptic dysfunction, they found a rapid decrease in PIP2 levels of about 40 percent, which persisted over days. Removal of Aβ re-established normal levels of PIP2 suggesting that the effect was reversible. Moreover, the decrease was specific for PIP2 and for oligomers, since monomeric and fibrillar Aβ failed to evoke it. This effect was blocked by treatment with scyllo-inositol, a compound that has been found to destabilize oligomers of Aβ and an antibody against Aβ oligomers (6E10) both of which interfere with the ability of oligomers to cause synaptic dysfunction [4–6]). The use of scyllo-inositol and immunotherapy are currently in human clinical trials as anti-amyloid therapies (see http://clinicaltrials.gov/ct2/show/NCT00568776?term=alzheimer&spons=elan&rank=2 and http://clinicaltrials.gov/ct2/show/NCT00299988?cond=%22Alzheimer+Disease%22&rank=213, respectively). The reduction in 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 also partially reversed by NMDA receptor blockade. The authors reasoned that if PIP2 deficiency is important in Aβ-induced synaptic impairment, then finding a way to elevate PIP2 might rescue the impaired synaptic function. For this, the authors turned to a genetic mouse model that expresses only half the amount of the major PIP2-phosphatase, synaptojanin (the underlying gene, SYNJ1, maps to human chromosome 21 and is thus a candidate for involvement in Down’s syndrome, another disorder with cognitive loss and altered PIP2 metabolism ). Berman and colleagues found that neurons from those mice were resistant to PIP2 depletion by Aβ oligomers. Furthermore, they demonstrated that Aβ was no longer able to inhibit LTP in hippocampal slices from synaptojanin-reduced mice.
PIP2 is central to many essential processes in neurons hence, changes in the levels of PIP2 in response to oligomeric Aβ could explain many of the phenotypes that have been observed by several researchers with oligomeric Aβ. The data 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-induced synaptic impairment.