A Peptide Motif Covering Splice Site B in Neuroligin-1 Binds to Aβ and Acts as a Neprilysin Inhibitor

The most common cause of dementia among elderly people is Alzheimer's disease (AD). The typical symptom of AD is the decline of cognitive abilities, which is caused by loss of synaptic function. Amyloid-β (Aβ) oligomers play a significant role in the development of this synaptic dysfunction. Neuroligin-(NL)1 is a postsynaptic cell-adhesion molecule located in excitatory synapses and involved in the maintenance and modulation of synaptic contacts. A recent study has found that Aβ interacts with the soluble N-terminal fragment of NL1. The present study aimed to elucidate the role of NL1 in Aβ-induced neuropathology. Employing surface plasmon resonance and competitive ELISA, we confirmed the high-affinity binding of NL1 to the Aβ peptide. We also identified a sequence motif representing the NL1-binding site for the Aβ peptide and showed that a synthetic peptide modeled after this motif, termed neurolide, binds to the Aβ peptide with high affinity, comparable to the NL1-Aβ interaction. To assess the effect of neurolide in vivo, wild-type and 5XFAD mice were subcutaneously treated with this peptide for 10 weeks. We observed an increase in Aβ plaque formation in the cortex of neurolide-treated 5XFAD mice. Furthermore, we showed that neurolide reduces the activity of neprilysin, the predominant Aβ-degrading enzyme in the brain. Accordingly, we suggest that neurolide is the NL1-binding site for Aβ peptide, and acts as an inhibitor of neprilysin activity. Based on these data, we confirm the involvement of NL1 in the development of AD and suggest a mechanism for NL1-induced Aβ plaque formation.</p

Excessive novelty-induced c-Fos expression and altered neurogenesis in the hippocampus of GluA1 knockout mice

a−Amino−3−hydroxy−5−methyl−4−isoxazolepropionic acid (AMPA) receptor GluA1 subunit−deficient (GluA1) / )) mice display noveltyinduced hyperactivity, cognitive and social defects and may model psychiatric disorders, such as schizophrenia and depression / mania. We used c−Fos expression in GluA1) / ) mice to identify brain regions responsible for novelty−induced hyperlocomotion. Exposure to a novel cage for 2 h significantly increased c−Fos expression in many brain regions in both wild−type and knockout mice. Interestingly, the clearest genotype effect was observed in the hippocampus and its main input region, the entorhinal cortex, where the novelty−induced c−Fos expression was more strongly enhanced in GluA1) / ) mice. Their novelty−induced hyperlocomotion partly depended on the activity of AMPA receptors, as it was diminished by the AMPA receptor antagonist 2,3−dioxo−6−nitro−1,2,3,4− tetrahydrobenzo[f]quinoxaline−7−sulphonamide (NBQX) and unaffected by the AMPA receptor potentiator 2,3−dihydro−1,4−benzodioxin− 6−yl−1−piperidinylmethanone (CX546). The hyperlocomotion of GluA1) / ) mice was normalised to the level of wild−type mice within 5−6 h, after which their locomotion followed normal circadian rhythm and was not affected by acute or chronic treatments with the selective serotonin reuptake inhibitor escitalopram. We propose that hippocampal dysfunction, as evidenced by the excessive c− Fos response to novelty, is the major contributor to novelty−induced hyperlocomotion in GluA1) / ) mice. Hippocampal dysfunction was also indicated by changes in proliferation and survival of adult−born dentate gyrus cells in the knockout mice. These results suggest focusing on the functions of hippocampal formation, such as novelty detection, when using the GluA1) / ) mouse line as a model for neuropsychiatric and cognitive disorder

Deficiency of prolyl oligopeptidase in mice disturbs synaptic plasticity and reduces anxiety-like behaviour, body weight, and brain volume

Prolyl oligopeptidase (PREP) has been implicated in neurodegeneration and neuroinflammation and has been considered a drug target to enhance memory in dementia. However, the true physiological role of PREP is not yet understood. In this paper, we report the phenotyping of a mouse line where the PREP gene has been knocked out. This work indicates that the lack of PREP in mice causes reduced anxiety but also hyperactivity. The cortical volumes of PREP knockout mice were smaller than those of wild type littermates. Additionally, we found increased expression of diazepam binding inhibitor protein in the cortex and of the somatostatin receptor-2 in the hippocampus of PREP knockout mice. Furthermore, immunohistochemistry and tail suspension test revealed lack of response of PREP knockout mice to lipopolysaccharide insult. Further analysis revealed significantly increased levels of polysialylated-neural cell adhesion molecule in PREP deficient mice. These findings might be explained as possible alteration in brain plasticity caused by PREP deficiency, which in turn affect behaviour and brain development