miR-429-3p mediates memory decline by targeting MKP-1 to reduce surface GluA1-containing AMPA receptors in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a leading cause of dementia in the elderly. Mitogen-activated protein kinase phosphatase 1 (MKP-1) plays a neuroprotective role in AD. However, the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively studied. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, thereby repressing mRNA translation. Here, we reported that the microRNA-429-3p (miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2AAPP AD model cells. We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3'-untranslated region (3' UTR). Inhibition of miR-429-3p by its antagomir (A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aß accumulation. More importantly, intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase (ERK1/2)-mediated GluA1 hyperphosphorylation at Ser831 site, thereby increasing the surface expression of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Together, these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice, suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.

Fangchinoline alleviates cognitive impairments through enhancing autophagy and mitigating oxidative stress in Alzheimer's disease models.

Introduction: Alzheimer's disease (AD) is a debilitating, progressive, neurodegenerative disorder characterized by the deposition of amyloid-ß (Aß) peptides and subsequent oxidative stress, resulting in a cascade of cytotoxic effects. Fangchinoline (Fan), a bisbenzylisoquinoline alkaloid isolated from traditional Chinese herb Stephania tetrandra S. Moorec, has been reported to possess multiple potent biological activities, including anti-inflammatory and antioxidant properties. However, the potential neuroprotective efficacy of Fan against AD remains unknown. Methods: N2AAPP cells, the mouse neuroblastoma N2A cells stably transfected with human Swedish mutant APP695, were served as an in vitro AD model. A mouse model of AD was constructed by microinjection of Aß1-42 peptides into lateral ventricle of WT mice. The neuroprotective effects of Fan on AD were investigated through a combination of Western blot analysis, immunoprecipitation and behavioral assessments. Results and discussion: It was found that Fan effectively attenuated the amyloidogenic processing of APP by augmenting autophagy and subsequently fostering lysosomal degradation of BACE1 in N2AAPP cells, as reflected by the decrease in P62 levels, concomitant with the increase in Beclin-1 and LC3-II levels. More importantly, Fan significantly ameliorated cognitive impairment in an Aß1-42-induced mouse model of AD via the induction of autophagy and the inhibition of oxidative stress, as evidenced by an increase in antioxidants including glutathione reductase (GR), total antioxidant capacity (T-AOC), nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and superoxide dismutase-1 (SOD-1) and a decrease in pro-oxidants including hydrogen peroxide (H2O2) and inducible nitric oxide synthase (i-NOS), coupled with a reduction in apoptosis marker, cleaved caspase-3. Taken together, our study demonstrate that Fan ameliorates cognitive dysfunction through promoting autophagy and mitigating oxidative stress, making it a potential therapeutic agent for AD.

Genetic inhibition of glutamate allosteric potentiation of GABAARs in mice results in hyperexcitability, leading to neurobehavioral abnormalities.

The imbalance between neuronal excitation and inhibition (E/I) in neural circuit has been considered to be at the root of numerous brain disorders. We recently reported a novel feedback crosstalk between the excitatory neurotransmitter glutamate and inhibitory γ-aminobutyric acid type A receptor (GABAAR)-glutamate allosteric potentiation of GABAAR functions through a direct binding of glutamate to the GABAAR itself. Here, we investigated the physiological significance and pathological implications of this cross-talk by generating the ß3E182G knock-in (KI) mice. We found that ß3E182G KI, while had little effect on basal GABAAR-mediated synaptic transmission, significantly reduced glutamate potentiation of GABAAR-mediated responses. These KI mice displayed lower thresholds for noxious stimuli, higher susceptibility to seizures and enhanced hippocampus-related learning and memory. Additionally, the KI mice exhibited impaired social interactions and decreased anxiety-like behaviors. Importantly, hippocampal overexpression of wild-type ß3-containing GABAARs was sufficient to rescue the deficits of glutamate potentiation of GABAAR-mediated responses, hippocampus-related behavioral abnormalities of increased epileptic susceptibility, and impaired social interactions. Our data indicate that the novel crosstalk among excitatory glutamate and inhibitory GABAAR functions as a homeostatic mechanism in fine-tuning neuronal E/I balance, thereby playing an essential role in ensuring normal brain functioning.

Octadecaneuropeptide Ameliorates Cognitive Impairments Through Inhibiting Oxidative Stress in Alzheimer's Disease Models.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-ß peptide (Aß) deposition. Aß accumulation induces oxidative stress, leading to mitochondrial dysfunction, apoptosis, and so forth. Octadecaneuropeptide (ODN), a diazepam-binding inhibitor (DBI)-derived peptide, has been reported to have antioxidant properties. However, it is unclear whether ODN has neuroprotective effects in AD. OBJECTIVE: To profile the potential effects of ODN on AD. METHODS: We established a mouse model of AD via microinjection of Aß in the lateral ventricle. Utilizing a combination of western blotting assays, electrophysiological recordings, and behavioral tests, we investigated the neuroprotective effects of ODN on AD. RESULTS: DBI expression was decreased in AD model mice and cells. Meanwhile, ODN decreased Aß generation by downregulating amyloidogenic AßPP processing in HEK-293 cells stably expressing human Swedish mutant APP695 and BACE1 (2EB2). Moreover, ODN could inhibit Aß-induced oxidative stress in primary cultured cells and mice, as reflected by a dramatic increase in antioxidants and a decrease in pro-oxidants. We also found that ODN could reduce oxidative stress-induced apoptosis by restoring mitochondrial membrane potential, intracellular Ca2+ and cleaved caspase-3 levels in Aß-treated primary cultured cells and mice. More importantly, intracerebroventricular injection of ODN attenuated cognitive impairments as well as long-term potentiation in Aß-treated mice. CONCLUSION: These results suggest that ODN may exert a potent neuroprotective effect against Aß-induced neurotoxicity and memory decline via its antioxidant effects, indicating that ODN may be a potential therapeutic agent for AD.

Biomimetic supramolecular polyurethane with sliding polyrotaxane and disulfide bonds for strain sensors with wide sensing range and self-healing capability.

To prolong the service life of flexible electronic materials, polymeric matrixes with excellent self-healing capability and integrated mechanical properties are highly desirable, but the balance between the self-healing capability and mechanical properties is a grand challenge. Here, polyrotaxanes as sliding crosslinkers and dynamic disulfide bonds are incorporated into the main chains of polyurethane (PU) via one-pot synthesis, which endows the PU with polydisperse hard/soft segments, high density of self-healing points and energy dissipation. Based on this judicious molecular design, the PU elastomers exhibit exceptional mechanical properties, such as high stretchability (1167 % with a tensile strength of 3.49 MPa), high fracture energy (20,775 J m-2) and high puncture energy (200.70 mJ). Moreover, due to the presence of dynamic reversible hydrogen and disulfide bonds, the elastomer could achieve stress and strain repair efficiencies of 93.98 % and 99.21 % at 100 ℃ within 1 h, respectively. The above-mentioned superiorities enable the bioinspired strain sensors to possess a large sensing range (∼596 %), high sensitivity (∼79.98), short response time (∼128 ms), along with excellent reliability and self-healing ability. Besides, the strain sensor exhibits remarkable recyclability and prominent reprocessability, which nicely solves the pollution by discarded electronics.

Polyhedral Oligomeric Silsesquioxane Encountering Tannic Acid: A Mild and Efficient Strategy for Interface Modification on Carbon Fiber Composites.

Designing and controlling the interfacial chemistry and microstructure of the carbon fiber is an important step in the surface modification and preparation of high-performance composites. To address this issue, a tannic acid (TA)/polyhedral oligomeric silsesquioxane (POSS) hybrid microstructure, similar to the topological structure, is designed on the fiber surface by one-pot synthesis under mild conditions. Fourier transform infrared (FT-IR), X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM) show that the functionality and surface roughness of the fiber are significantly broadened. Correspondingly, the tensile strength (TS) of CF-TA/POSS100 and interlaminar shear strength (ILSS) of CF-TA/POSS100-based composites increased by 18 and 34%, respectively. Following that, a failure mechanism study is conducted to demonstrate the interphase structure containing TA/POSS, which is quite critical in optimizing the mechanical performance of the multiscale composites. Moreover, the strategy for the use of TA for constructing a robust coating to replace the traditional modification without affecting the fiber intrinsic strength is an improved design and provides a new idea for the development of high-performance composites.