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Cholinergic neurons in the basal forebrain constitute a major source of cholinergic inputs to the forebrain, modulate diverse functions including sensory processing, memory and attention, and are vulnerable to Alzheimer's disease (AD). Recently, we classified cholinergic neurons into two distinct subpopulations; calbindin D28K-expressing (D28K+) versus D28K-lacking (D28K−) neurons. Yet, which of these two cholinergic subpopulations are selectively degenerated in AD and the molecular mechanisms underlying this selective degeneration remain unknown. Here, we reported a discovery that D28K+ neurons are selectively degenerated and this degeneration induces anxiety-like behaviors in the early stage of AD. Neuronal type specific deletion of NRADD effectively rescues D28K+ neuronal degeneration, whereas genetic introduction of exogenous NRADD causes D28K− neuronal loss. This gain- and loss-of-function study reveals a subtype specific degeneration of cholinergic neurons in the disease progression of AD and hence warrants a novel molecular target for AD therapy.

Long non-coding RNA (lncRNA) is a kind of non-coding RNA (ncRNA), with a length of 200 nt to 100 kb, that lacks a significant open reading frame (ORF) encoding a protein. lncRNAs are widely implicated in various physiological and pathological processes, such as epigenetic regulation, cell cycle regulation, cell differentiation regulation, cancer, and neurodegenerative diseases, through their interactions with chromatin, protein, and other RNAs. Numerous studies have suggested that lncRNAs are closely linked with the occurrence and development of a variety of diseases, especially neurodegenerative diseases, of which the etiologies are complicated and the underlying mechanisms remain elusive. Determining the roles of lncRNA in the pathogenesis of neurodegenerative diseases will not only deepen understanding of the physiological and pathological processes that occur in those diseases but also provide new ideas and solutions for their diagnosis and prevention. This review aims to highlight the progress of lncRNA research in the pathological and behavioral changes of neurodegenerative diseases. Specifically, we focus on how lncRNA dysfunctions are involved in the pathogenesis of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.

The PSD-95/SAPAP/Shank complex functions as the major scaffold in orchestrating the formation and plasticity of the post-synaptic densities (PSDs). We previously demonstrated that the exquisitely specific SAPAP/Shank interaction is critical for Shank synaptic targeting and Shank-mediated synaptogenesis. Here, we show that the PSD-95/SAPAP interaction, SAPAP synaptic targeting, and SAPAP-mediated synaptogenesis require phosphorylation of the N-terminal repeat sequences of SAPAPs. The atomic structure of the PSD-95 guanylate kinase (GK) in complex with a phosphor-SAPAP repeat peptide, together with biochemical studies, reveals the molecular mechanism underlying the phosphorylation-dependent PSD-95/SAPAP interaction, and it also provides an explanation of a PSD-95 mutation found in patients with intellectual disabilities. Guided by the structural data, we developed potent non-phosphorylated GK inhibitory peptides capable of blocking the PSD-95/SAPAP interaction and interfering with PSD-95/SAPAP-mediated synaptic maturation and strength. These peptides are genetically encodable for investigating the functions of the PSD-95/SAPAP interaction in vivo.

We investigated the thermal properties of few-layer Mo0.5W0.5S2 using a series of samples with different kinds of capping layers. Temperature-dependent Raman measurements were conducted in the range of 300–500 K, with power-dependent measurements also carried out. It indicated, for the few-layer Mo0.5W0.5S2, the temperature coefficients of the WS2-like E12g mode, MoS2-like E12g mode and A1g mode were −0.0155 cm−1/K, −0.0146 cm−1/K, and −0.0130 cm−1/K, respectively. And the thermal conductivity was estimated to be 44.8 W/mK. Moreover, the Mo0.5W0.5S2 samples coated with capping layers (ZrO2, HfO2) both showed a better thermal stability and a larger thermal conductivity than the one without. The results revealed that the capping layer should be an important factor in the thermal property. Keywords: Mo0.5W0.5S2, TMDs, Thermal properties, High temperature, Capping layers, Raman

Summary: Kibra is a synaptic scaffold protein regulating learning and memory. Alterations of Kibra-encoding gene WWC1 cause various neuronal disorders, including Alzheimer’s disease and Tourette syndrome. However, the molecular mechanism underlying Kibra’s function in neurons is poorly understood. Here we discover that Kibra, via its N-terminal WW12 tandem domains, binds to a postsynaptic density enriched protein, Dendrin, with a nanomolar dissociation constant. On the basis of the structure of Kibra WW12 in complex with Dendrin PY motifs, we developed a potent peptide inhibitor capable of specifically blocking the binding between Kibra and Dendrin in neurons. Systematic administration of the inhibitory peptide attenuated excitatory synaptic transmission, completely blocked long-term potentiation induction, and impaired spatial learning and memory. A Kibra mutation found in Tourette syndrome patients causes defects in binding to Dendrin. Thus, Kibra can modulate spatial learning and memory via binding to Dendrin. : Ji et al. report that the memory-related molecule Kibra, via its WW tandem domains, specifically binds to the synaptic protein Dendrin with a low-nanomolar dissociation constant to modulate spatial learning and memory. Keywords: Kibra, Dendrin, WW domains, tandem repeats, scaffold protein, synaptic complex, synaptic transmission, learning and memory, psychiatric disorder, Tourette syndrome

Summary: Retroactive interference (RI) occurs when new incoming information impairs an existing memory, which is one of the primary sources of forgetting. Although long-term potentiation (LTP) reversal shows promise as the underlying neural correlate, the key molecules that control the sensitivity of memory circuits to RI are unknown, and the developmental trajectory of RI effects is unclear. Here we found that depotentiation in the hippocampal dentate gyrus (DG) depends on GluN2A-containing NMDA receptors (NMDARs). The susceptibility of LTP to disruption progressively increases with the rise in the GluN2A/GluN2B ratio during development. The vulnerability of hippocampus-dependent memory to interference from post-learning novelty exploration is subject to similar developmental regulation by NMDARs. Both GluN2A overexpression and GluN2B downregulation in the DG promote RI-induced forgetting. Altogether, our results suggest that a switch in GluN2 subunit predominance may confer age-related differences to depotentiation and underlie the developmental decline in memory resistance to RI. : Ge et al. report that the NMDA receptor GluN2A/GluN2B subunit ratio determines the sensitivity of strengthened neuronal connections to depotentiation. As the ratio rises during development, memories become more vulnerable to disruption by post-learning interference. These findings help to illuminate the mechanism by which forgetting rates may vary with age. Keywords: forgetting, retroactive interference, depotentiation, NMDA receptor

Ginsenoside compound K (GCK), the main metabolite of protopanaxadiol constituents of Panax ginseng, easily produces alkali metal adduct ions during mass spectrometry particularly with lithium. Accordingly, we have developed a rapid and sensitive liquid chromatography–tandem mass spectrometric method for analysis of GCK in human plasma based on formation of a lithium adduct. The analyte and paclitaxel (internal standard) were extracted from 50 µL human plasma using methyl tert-butyl ether. Chromatographic separation was performed on a Phenomenex Gemini C18 column (50 mm×2.0 mm; 5 μm) using stepwise gradient elution with acetonitrile–water and 0.2 mmol/L lithium carbonate at a flow rate of 0.5 mL/min. Detection was performed in the positive ion mode using multiple reaction monitoring of the transitions at m/z 629→449 for the GCK-lithium adduct and m/z 860→292 for the adduct of paclitaxel. The assay was linear in the concentration range 1.00–1000 ng/mL (r2>0.9988) with intra- and inter-day precision of ±8.4% and accuracy in the range of −4.8% to 6.5%. Recovery, stability and matrix effects were all satisfactory. The method was successfully applied to a pharmacokinetic study involving administration of a single GCK 50 mg tablet to healthy Chinese volunteers.