Reelin signaling antagonizes β-amyloid at the synapse

Abstract

Abnormal processing of the amyloid precursor protein (APP) and ␤-amyloid (A␤) plaque accumulation are defining features of Alzheimer disease (AD), a genetically complex neurodegenerative disease that is characterized by progressive synapse loss and neuronal cell death. A␤ induces synaptic dysfunction in part by altering the endocytosis and trafficking of AMPA and NMDA receptors. Reelin is a neuromodulator that increases glutamatergic neurotransmission by signaling through the postsynaptic ApoE receptors Apoer2 and Vldlr and thereby potently enhances synaptic plasticity. Here we show that Reelin can prevent the suppression of long-term potentiation and NMDA receptors, which is induced by levels of A␤ comparable to those present in an AD-afflicted brain. This reversal is dependent upon the activation of Src family tyrosine kinases. At high concentrations of A␤ peptides, Reelin can no longer overcome the A␤ induced functional suppression and this coincides with a complete blockade of the Reelin-dependent phosphorylation of NR2 subunits. We propose a model in which A␤, Reelin, and ApoE receptors modulate neurotransmission and thus synaptic stability as opposing regulators of synaptic gain control.Alzheimer disease ͉ apolipoprotein E ͉ long-term potentiation ͉ NMDA receptor ͉ A␤ oligomer A lzheimer disease (AD) is a complex genetic neurodegenerative disease that afflicts an increasing fraction of our aging population (1). A characteristic feature of AD is the accumulation of oligomeric and higher-order aggregates of the A␤ 1-42 form of the amyloid-␤ (A␤) peptide, which is physiologically released by sequential proteolytic cleavage from the amyloid-␤ precursor protein (APP) (2, 3). Abnormal, amyloidogenic A␤ processing and plaque formation progressively lead to synaptic dysfunction, synapse loss, and ultimately neuronal death.Recent insight into the pathophysiological functions of A␤ came from studies that demonstrated a potent negative impact of A␤ oligomers on synaptic functions that underlie long-term synaptic plasticity (4-6). Incubation of hippocampal neurons and slices with A␤ oligomers leads to intracellular trapping or functional impairment of AMPA and NMDA-type glutamate receptors (7-9), thereby decreasing long-term potentiation (LTP), an enhancement of synaptic strength that is correlated with memory (4, 5, 10-13). Consistent with these in vitro findings, Palop et al. (14,15) showed that overexpression of mutant APP forms in mice resulted in a global dysregulation of neuronal network activity in vivo.Reelin is a signaling protein that is produced by interneurons in the brain and that has an effect on synaptic functions that is opposite to that of A␤ oligomers. Reelin addition to hippocampal slices results in enhanced LTP (16) as a result of the activation of Src family tyrosine kinases (SFKs) (17-19), which increase NMDA receptor activity by tyrosine phosphorylation of their NR2 subunits (20,21). These effects of Reelin are mediated by a pair of homologous cell surface receptors designated apolipoprotein E r...

ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling

“…Activation of Reelin signaling at the synapse can prevent β-amyloid-induced LTP suppression (13). To test ability of Reelin to maintain normal hippocampal LTP in the presence of naturally occurring oligomeric Aβ, we perfused hippocampal slices from the different ApoE knockin mice with ACSF containing either brain extract from a human non-AD case (Fig.…”

“…Aβ oligomers potently suppress synaptic functions and impair synaptic plasticity (reviewed in ref. 21), and we have recently shown that Reelin signaling through Apoer2 can prevent the Aβ oligomer-induced inhibition of NMDA receptors at the synapse (13).…”

“…By contrast, amyloid-β peptide (Aβ) induces NMDA receptor-dependent synaptic suppression (11) by decreasing GluN2 tyrosine phosphorylation and increasing endocytosis of the NMDA receptor (12). Reelin and ApoE receptors thus function together to reverse this NMDA receptordependent synaptic suppression by doing the opposite-i.e., increasing GluN2 tyrosine phosphorylation (8,10) and thereby maintaining active NMDA receptors at the neuronal surface (13).…”

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…Other potential mechanisms by which ApoE receptors may promote neuronal survival (Beffert et al 2006b) during aging involve signaling pathways that control microtubule and actin dynamics Assadi et al 2003;Brich et al 2003;Ohkubo et al 2003;Chai et al 2009;Forster et al 2010;Rust et al 2010), dendritogenesis (Niu et al 2004), spine formation (Niu et al 2008), glutamate receptor function and synaptic plasticity (Zhuo et al 2000;Weeber et al 2002;Beffert et al 2005;Chen et al 2005;D'Arcangelo 2005;Sinagra et al 2005;Groc et al 2007;Durakoglugil et al 2009;Korwek et al 2009;Chen et al 2010), as well as learning and memory (reviewed in Herz and Beffert 2000;Herz and Chen 2006;Bu 2009;Herz 2009). In this section we will mainly focus on the role of the ApoE receptors Apoer2 and Vldlr and their ligand Reelin in these processes.…”

“…Moreover, Reelin signaling activates SFKs , which would directly oppose the activity of the phosphatases on the NMDA receptor (Snyder et al 2005). This hypothesis was tested by measuring the effect of different Ab preparations, including Ab-containing extracts from human AD brain, on hippocampal synaptic plasticity, NMDA receptor tyrosine phosphorylation, and activity in response to Reelin (Durakoglugil et al 2009). At low to intermediate, but not at unphysiologically high (.400 nM) Ab concentrations, activation of Reelin signaling can completely prevent the synaptic suppression induced by the oligomers, suggesting that Reelin is a physiological mediator of neuroprotection.…”