This study convincingly demonstrates that PAR-1 phosphorylation of Dlg reduces the amount of Dlg localized to postsynaptic sites, and consequently decreases excitatory transmission. PAR-1 and Dlg are the fly homologs of mammalian proteins MARK and PSD-95, respectively. In mice, knocking out PSD-95 decreases excitatory transmission through the selective removal of AMPA-type glutamate receptors at synapses (Beique et al., 2006). Curiously, elevated levels of amyloid-β have been linked to reductions in levels of synaptic PSD-95 (Gylys et al., 2004; Almeida et al., 2005; Roselli et al., 2005) and surface AMPA receptors (Almeida et al., 2005; Roselli et al., 2005; Hsieh et al., 2006), and also to depression of AMPA receptor-mediated synaptic transmission (Kamenetz et al., 2003; Hsieh et al., 2006; Ting et al., 2006). Together these findings raise the possibility that elevated levels of amyloid-β could be decreasing excitatory transmission in AD by activating MARK, leading to phosphorylation of PSD-95 and subsequent removal of synaptic AMPA receptors.

Although PAR-1/MARK have...  Read more

This study convincingly demonstrates that PAR-1 phosphorylation of Dlg reduces the amount of Dlg localized to postsynaptic sites, and consequently decreases excitatory transmission. PAR-1 and Dlg are the fly homologs of mammalian proteins MARK and PSD-95, respectively. In mice, knocking out PSD-95 decreases excitatory transmission through the selective removal of AMPA-type glutamate receptors at synapses (Beique et al., 2006). Curiously, elevated levels of amyloid-β have been linked to reductions in levels of synaptic PSD-95 (Gylys et al., 2004; Almeida et al., 2005; Roselli et al., 2005) and surface AMPA receptors (Almeida et al., 2005; Roselli et al., 2005; Hsieh et al., 2006), and also to depression of AMPA receptor-mediated synaptic transmission (Kamenetz et al., 2003; Hsieh et al., 2006; Ting et al., 2006). Together these findings raise the possibility that elevated levels of amyloid-β could be decreasing excitatory transmission in AD by activating MARK, leading to phosphorylation of PSD-95 and subsequent removal of synaptic AMPA receptors.

Although PAR-1/MARK have been shown to phosphorylate tau, this does not seem to be playing a role in the synaptic effects observed by Zhang et al., because effects of PAR-1 upregulation were blocked by expression of a non-phosphorylatable variant of Dlg, and were reproduced by expression of a phospho-mimetic variant of Dlg.

References:
Almeida CG, Tampellini D, Takahashi RH, Greengard P, Lin MT, Snyder EM, Gouras GK. Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Neurobiol Dis. 2005 Nov;20(2):187-98. Abstract

Beique JC, Lin DT, Kang MG, Aizawa H, Takamiya K, Huganir RL. Synapse-specific regulation of AMPA receptor function by PSD-95. Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19535-40. Epub 2006 Dec 5. Abstract

Gylys KH, Fein JA, Yang F, Wiley DJ, Miller CA, Cole GM. Synaptic changes in Alzheimer's disease: increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence. Am J Pathol. 2004 Nov;165(5):1809-17. Abstract

Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, Malinow R. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron. 2006 Dec 7;52(5):831-43. Abstract

Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R. APP processing and synaptic function. Neuron. 2003 Mar 27;37(6):925-37. Abstract

Roselli F, Tirard M, Lu J, Hutzler P, Lamberti P, Livrea P, Morabito M, Almeida OF. Soluble beta-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses. J Neurosci. 2005 Nov 30;25(48):11061-70. Abstract

Ting JT, Kelley BG, Lambert TJ, Cook DG, Sullivan JM. Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms. Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):353-8. Epub 2006 Dec 21. Abstract

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