The role of STEP in Alzheimer's disease

Child Study Center, Yale University School of Medicine, New Haven, CT, USA.
Channels (Austin, Tex.) (Impact Factor: 2.32). 09/2010; 4(5):347-50. DOI: 10.4161/chan.4.5.12910
Source: PubMed


Amyloid beta (Aβ), the putative causative agent in Alzheimer's disease, is known to affect glutamate receptor trafficking. Previous studies have shown that Aβ downregulates the surface expression of N-methyl D-aspartate type glutamate receptors (NMDARs) by the activation of STriatal-Enriched protein tyrosine Phosphatase 61 (STEP₆₁). More recent findings confirm that STEP₆₁ plays an important role in Aβ-induced NMDAR endocytosis. STEP levels are elevated in human AD prefrontal cortex and in the cortex of several AD mouse models. The increase in STEP₆₁ levels and activity contribute to the removal of GluN1/GluN2B receptor complexes from the neuronal surface membranes. The elevation of STEP₆₁ is due to disruption in the normal degradation of STEP₆₁ by the ubiquitin proteasome system. Here, we briefly discuss additional studies in support of our hypothesis that STEP₆₁ contributes to aspects of the pathophysiology in Alzheimer's disease. Exogenous application of Aβ-enriched conditioned medium (7PA2-CM) to wild-type cortical cultures results in a loss of GluN1/GluN2B subunits from neuronal membranes. Abeta-mediated NMDAR internalization does not occur in STEP knock-out cultures, but is rescued by the addition of active TAT-STEP to the cultures prior to Aβ treatment.

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    • "Additionally to a decrease in mRNA levels, the decrease in GluN2B and GluN2A subunits could be due also to a decrease in reelin levels, a protein that mediates NMDAR activity, and which is depleted in AD brains (Herring et al., 2012). On the other hand, the decrease in NMDAR subunits may also be due to an increase in STEP 61 , which contributes to the endocytosis of GluN1/GluN2B and GluN1/GluN2A receptors (Snyder et al., 2005; Kurup et al., 2010). "
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    ABSTRACT: Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly. Alterations capable of causing brain circuitry dysfunctions in AD may take several years to develop. Oligomeric amyloid-beta peptide (Aβ) plays a complex role in the molecular events that lead to progressive loss of function and eventually to neurodegeneration in this devastating disease. Moreover, N-methyl-D-aspartate (NMDA) receptors (NMDARs) activation has been recently implicated in AD-related synaptic dysfunction. Thus, in this review we focus on glutamatergic neurotransmission impairment and the changes in NMDAR regulation in AD, following the description on the role and location of NMDARs at pre- and post-synaptic sites under physiological conditions. In addition, considering that there is currently no effective ways to cure AD or stop its progression, we further discuss the relevance of NMDARs antagonists to prevent AD symptomatology. This review posits additional information on the role played by Aβ in AD and the importance of targeting the tripartite glutamatergic synapse in early asymptomatic and possible reversible stages of the disease through preventive and/or disease-modifying therapeutic strategies.
    Neuropharmacology 08/2013; A). DOI:10.1016/j.neuropharm.2013.08.013 · 5.11 Impact Factor
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    • "Mechanistically, activation of phosphatases in AbO-exposed neurons appears to underlie removal of glutamate receptors from synapses. Kurup et al. (2010) have proposed a mechanism in which phosphatase STEP(61) mediates Ab-induced NMDAR removal from synaptic membranes. Fyn activation was also proposed to occur in response to Ab-PrP C interaction, yielding phosphorylation of the NR2B subunit of NMDARs, leading to loss of surface NMDARs (Um et al. 2012). "
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    ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia in the elderly. Memory loss in AD is increasingly attributed to soluble oligomers of the amyloid-β peptide (AβOs), toxins that accumulate in AD brains and target particular synapses. Glutamate receptors appear to be centrally involved in synaptic targeting by AβOs. Once bound to neurons, AβOs dysregulate the activity and reduce the surface expression of both N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) types of glutamate receptors, impairing signaling pathways involved in synaptic plasticity. In the extracellular milieu, AβOs promote accumulation of the excitatory amino acids, glutamate and D-serine. This leads to overactivation of glutamate receptors, triggering abnormal calcium signals with noxious impacts on neurons. Here, we review key findings linking AβOs to deregulated glutamate neurotransmission and implicating this as a primary mechanism of synapse failure in AD. We also discuss strategies to counteract the impact of AβOs on excitatory neurotransmission. In particular, we review evidence showing that inducing neuronal hyperpolarization via activation of inhibitory GABAA receptors prevents AβO-induced excitotoxicity, suggesting that this could comprise a possible therapeutic approach in AD. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 05/2013; 126(2). DOI:10.1111/jnc.12304 · 4.28 Impact Factor
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    • "Crosses between mice with the APP mutation and mice null for STEP produced progeny that no longer showed increased internalization of GluA1/GluA2 receptors, despite elevated levels of Ab. The work extends earlier studies demonstrating that STEP mediates the internalization of NMDAR complexes (Kurup et al. 2010a,b), and that genetic removal of STEP is sufficient to restore cognitive deficits in 6-month-old 3xTg-AD mice (Zhang et al. 2010). As later stages of AD are characterized by increased excitotoxicity and neuronal degeneration, the increased glutamate receptor levels in the absence of STEP are likely to have detrimental effects in more advanced AD, a hypothesis that needs to be experimentally tested in future studies. "
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    ABSTRACT: J. Neurochem. (2011) 119, 664–672. Striatal-Enriched protein tyrosine Phosphatase of MW 61 kDa (STEP61) is a protein tyrosine phosphatase recently implicated in the pathophysiology of Alzheimer’s disease (AD). STEP61 is elevated in human AD prefrontal cortex and in the cortex of several AD mouse models. The elevated levels of active STEP61 down-regulate surface expression of GluN1/GluN2B (formerly NR1/NR2B) receptor complexes, while genetically reducing STEP levels rescues both the biochemical and cognitive deficits in a triple transgenic AD mouse model (3xTg-AD). Here, we show that increased STEP61 also plays a role in beta amyloid (Aβ)-mediated internalization of the α-amino-3-hydroxy-5-methyl-4-(AMPA) receptor (AMPAR) subunits GluA1/GluA2 (formerly GluR1/GluR2). We purified Aβ oligomers and determined that oligomers, but not monomers, lead to endocytosis of GluA1/GluA2 receptors in cortical cultures. The decrease in GluA1/GluA2 receptors is reversed in the progeny of STEP knock-out (KO) mice crossed with Tg2576 mice, despite elevated levels of Aβ. These results provide strong support for the hypothesis that STEP61 is required for Aβ-mediated internalization of GluA1/GluA2 receptors.
    Journal of Neurochemistry 10/2011; 119(3):664 - 672. DOI:10.1111/j.1471-4159.2011.07450.x · 4.28 Impact Factor
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