. A role for sorting nexin 27 in AMPA receptor trafficking. Nat Commun. 2014;5:3176. PubMed.


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  1. Is a deaf, blind neuron still a neuron?

    Increasing evidence suggests that synaptic dysfunction may contribute significantly to the learning and memory deficits that characterize Alzheimer’s disease and possibly Down’s syndrome, which always leads to AD pathology by age 40 and to dementia in ~50 percent of cases. For example, neuronal function depends critically on the correct localization and function of neurotransmitter and neurotrophin receptors, which are disrupted in AD, and the mechanism of this disruption is just now beginning to be elucidated (Tong et al., 2004; Almeida et al., 2005; Snyder et al., 2005; Abisambra et al., 2010; Liu et al., 2010).

    Two recent lines of investigation in particular have shed light on how dysfunction of neurotrophin and neurotransmitter receptors contributes to cognitive defects.  In one, it was found that genetic loss of sorting nexin 27, a regulator of endocytic sorting and trafficking, contributes to excitatory synaptic dysfunction by reducing NMDA and AMPA glutamate receptor recycling to the plasma membrane (Wang et al., 2013; Loo et al., 2014). Indeed, SNX27 and its regulator, the CCAAT/enhancer binding protein β (C/EBPβ), are downregulated in DS because the chromosome 21-encoded micro RNA miR-155 that negatively regulates C/EBPβ is overexpressed due to the extra copy of that chromosome.  Increasing expression of SNX27 in the hippocampus of Down's syndrome mice rescues both synaptic and cognitive deficits. In the most recent paper, Loo and colleagues report that the synaptic defect that results from loss of SNX27 is due to poor transfer of AMPA receptor subunits to the cell surface of dendritic spines. As a result, LTP, but not LTD, was completely abolished in hippocampal slices from SNX27-/- mice. 

    Second, we have found that either APP overexpression or exposure to the Aβ peptide prevent trafficking of the LDL, NMDA, and p75 receptors to their functional location on the cell surface. This leads to poor LDL uptake, poor neurite outgrowth in response to nerve growth factor, poor Ca2+ entry in response to glutamate, and inhibition of LTP (Abisambra et al., 2010; Ari et al., 2014).  The mechanism is evidently through Aβ’s inhibition of certain microtubule (MT) motors, specifically kinesin 5 (also termed Eg5 or kif11), which are required for MT-dependent transport of many cellular structures, and whose inhibition by Aβ leads to poor receptor trafficking (Borysov et al., 2011; Ari et al., 2014).  Aβ inhibition of kinesin 5 and other MT motors also leads to chromosome mis-segregation and observed aneuploidy of more than 20 percent, including almost 10 percent trisomy 21 mosaicism in the brains of AD patients, and in mouse and cell models thereof (Granic et al., 2009; Iourov et al., 2009; Arendt et al., 2010). Monastrol, a specific inhibitor of kinesin 5 (Eg5), also causes chromosome  mis-segregation and neurotrophin and neurotransmitter mislocalization and dysfunction, reinforcing kinesin 5 as an important Aβ interacting protein (Borysov et al., 2011; Ari et al., 2014). The pathogenic interaction between Aβ and kinesin 5 may be a good target for therapeutic intervention.

    In sum, gene dosage changes in Down's syndrome and/or Alzheimer’s disease may lead to neurotransmitter and neurotrophin receptor mislocalization and consequent dysfunction by two mechanisms, SNX27 downregulation or Aβ upregulation, both of which would have profound consequences for learning and memory.


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