Amyloid-β Synaptojanin Protects Synaptic Function

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

Alzheimer’s disease (AD) is associated with the accumulation of aggregates of insoluble amyloid-β (Aβ) protein, in particular Aβ42, which is released from the membrane-bound amyloid precursor protein by the proteases β- and -secretase. Oligomeric Aβ42 alters synaptic activity by affecting glutamate receptor abundance at synaptic membranes and reducing the number of dendritic spines, but its effects on intracellular signaling are unclear. Berman et al. had previously shown that mutations in genes encoding components of the -secretase complex are linked to abnormal metabolism of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P₂]. Here, they showed that exposure of mouse cortical neurons to a preparation of oligomeric Aβ42 or to cell-derived Aβ42 reduced the abundance of membrane PtdIns(4,5)P₂ compared with that in control neurons, as measured by high-performance liquid chromatography. This Aβ42-dependent reduction of membrane PtdIns(4,5)P₂ abundance was blocked when extracellular Ca²⁺ was chelated by EGTA or when neurons were treated with an antibody against Aβ. The membrane localization of a fluorescent PtdIns(4,5)P₂-binding protein was lower in Aβ42-treated PC12 cells than in control cells; however, an inhibitor of phospholipase C, which hydrolyzes PtdIns(4,5)P₂, restored membrane localization of the PtdIns(4,5)P₂ probe in Aβ42-treated cells. When neurons from mice heterozygous for the gene encoding the PtdIns(4,5)P₂ phosphatase synaptojanin 1 (Synj1^+/– mice) were treated with Aβ42, the abundance of membrane PtdIns(4,5)P₂ was unchanged. Furthermore, whereas long-term potentiation (LTP) in hippocampal slices of wild-type mice was inhibited by Aβ42 treatment, LTP in hippocampal slices from Synj1^+/– mice was unaffected. Thus, Aβ42 appears to impair synaptic plasticity by reducing membrane PtdIns(4,5)P₂ abundance, an effect that is partly dependent on synaptojanin 1, whose inhibition may well prove beneficial in the treatment of AD.

D. E. Berman, C. Dall’Armi, S. V. Voronov, L. B. J. McIntire, H. Zhang, A. Z. Moore, A. Staniszewski, O. Arancio, T.-W. Kim, G. Di Paolo, Oligomeric amyloid-β peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism. Nat. Neurosci. 11, 547-554 (2008). [PubMed]