. Epigenetic suppression of neuroligin 1 underlies amyloid-induced memory deficiency. Nat Neurosci. 2014 Feb;17(2):223-31. Epub 2014 Jan 19 PubMed.

Recommends

Please login to recommend the paper.

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

  1. This study by Bie and colleagues is certainly very interesting. It nicely links microglia-mediated inflammation in general, i.e., irrespective of the cause/trigger of microglia activation, to epigenetic changes and subsequent phenotypes, including memory changes. Thus it brings yet another strong piece of evidence that neuroinflammation and microglia action impact neuronal function. However, the injection of synthetic Aβ peptides (apparently restricted to Aβ 1-40) does not represent the full picture and spectrum of Aβ and amyloid species found in AD. Thus, the described phenotype and mechanistic explanation needs to be confirmed at least in a transgenic AD model of cerebral amyloidosis and/or by using amyloid fibrils isolated from human or transgenic mouse AD brain. Moreover, this type of injection model rather mimics an acute injury, and the microglia only have short-term exposure to the Aβ, while the chronic and progressive nature of AD, even in mouse models, likely induces a different inflammatory response.

    In conclusion, I think these are very interesting and—in general—convincing findings. However, they describe a mechanism that may not necessarily account for AD, or at least needs to be tested more stringently in an AD context.

  2. Chronic neuroinflammation is a common feature of several degenerative disorders of the central nervous system, including amyotrophic lateral sclerosis, Parkinson´s disease, and Alzheimer´s disease. It is widely assumed that the sustained presence of inflammatory cytokines, chemokines, or radical oxygen species contribute to neuronal dysfunction and demise in these neurodegenerative diseases. Recent evidence suggests that microglial activation affects synaptic morphology and plasticity in AD. Precisely how inflammatory mediators affect neuronal function and morphology remains largely unknown.

    The present paper by Bie and colleagues investigates the effect of a direct injection of either fibrillar Aβ1-40 or bacterial lipopolysaccharide into the rat hippocampus, thereby modeling acute toll-like receptor 4 mediated brain inflammation. A key finding of this study shows that Aβ1-40 and LPS induce an upregulation of HDAC2 activity, which in turn leads to the suppression of neuroligin1. Neuroligin1, a postsynaptic protein, forms a complex with the presynaptic protein neurexin and this trans-synaptic complex contributes to synaptic plasticity and efficacy. Consequently, neuroligin1 reduction associated with suppression of long-term potentiation and impaired spatial memory tested by the Morris Water Maze paradigm. A cofactor for the HDAC2 induced transcriptional suppression of neuroligin1 is Mecp2, since administration of its siRNA decreased HDAC2 occupancy in the neuroligin- promoter region. Both Aβ1-40 and LPS injection caused acute microglial activation with an increase of CD11b positivity and interleukin-1β in the rat hippocampus. Microinjection of minocycline decreased both CD11b and interleukin-1β levels and restored neuroligin-1 mRNA and protein levels, thereby improving synapse function and spatial memory.

    This paper is important since it sheds further light on the mechanisms by which inflammatory molecules affect neuronal functions relevant for memory formation. It underlines that Aβ peptides, at least on an in-vivo level, may not affect synaptic function alone, but act through the release of inflammatory molecules by activated microglia. It stands in line with previous results showing that Aβ-evoked inflammation suppresses LTP also through the release of nitric oxide by NOS2 (Wang et al., 2004). Nevertheless, inflammatory mediators may affect more than one system relevant for synaptic functioning as indicated by a recent paper (see Tong et al., 2012). While the present mechanisms require further functional studies in models of chronic Aβ stimulation, the protective effect on innate immune blockade has already been shown in such models (Kummer et al., 2011Heneka et al., 2013). 

    References:

    . Beta-amyloid-mediated inhibition of NMDA receptor-dependent long-term potentiation induction involves activation of microglia and stimulation of inducible nitric oxide synthase and superoxide. J Neurosci. 2004 Jul 7;24(27):6049-56. PubMed.

    . Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-1β via p38 mitogen-activated protein kinase. J Neurosci. 2012 Dec 5;32(49):17714-24. PubMed.

    . Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation. Neuron. 2011 Sep 8;71(5):833-44. PubMed.

    . NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature. 2013 Jan 31;493(7434):674-8. PubMed.

  3. Several researchers have reported that Aβ fibrils affect synaptic plasticity, learning and memory in-vitro and in-vivo. However the precise mechanism of synaptic toxicity of Aβ remains elusive. Neuroligin 1 (NLG1) is one of the postsynaptic adhesion molecules bridging the synaptic cleft with its presynaptic ligand, neurexin. NLG1 has been implicated in the formation and stabilization of central glutamatergic synapses. Genetic studies revealed that NLG1 plays critical roles in the etiology of autism spectrum disorder and neuropsychiatric diseases. However, the pathophysiological role of NLG1 in Alzheimer disease still remains unknown.

    Bie et al. analyzed the Aβ-injected rat as the amyloid-induced memory deficiency model, and found that amyloid fibrils caused the synaptic dysfunction via epigenetic changes in the expression of NLG1. They also revealed that these changes are mediated through neuroinflammation pathway. The results presented here imply that the epigenetic mechanism links amyloid-induced neuroinflammation and synaptic dysfunction through the regulation of NLG1 expression.

    It would be interesting to study how much reduction in NLG1 expression is sufficient for the synaptic dysfunction. As NLG1 levels are regulated by epigenetic (this study), translational (Gkogkas et al., 2013), and proteolytic (Suzuki et al., 2012Peixoto et al., 2012) mechanisms, pharmacological modulation of these pathways might have a potential as anti-memory deficiency therapeutics. Also, it would be intriguing to analyze whether the other molecules regulated by MeCP2/HDAC2 complex are involved in the Aβ toxicity. In addition, analysis of NLG1 levels in the brains of preclinical AD, MCI and AD patients may provide an important information when and where the synaptic dysfunction by Aβ starts and spreads. In sum, this study supports the notion that the alterations in the synaptic adhesion molecules by amyloid fibrils or other insults play pathological roles in Alzheimer disease and neurodegenerative disease by disruption of connectome in human brains.

    References:

    . Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature. 2013 Jan 17;493(7432):371-7. Epub 2012 Nov 21 PubMed.

    . Activity-dependent proteolytic cleavage of neuroligin-1. Neuron. 2012 Oct 18;76(2):410-22. PubMed.

    . Transsynaptic signaling by activity-dependent cleavage of neuroligin-1. Neuron. 2012 Oct 18;76(2):396-409. PubMed.

This paper appears in the following:

News

  1. Could Silencing Neuroligin-1 Drive Synaptic Loss in AD?