Sulforaphane improved cognitive behavior in APP/PS1 mice via promoting structural and functional synaptic plasticity in the hippocampus.

Synaptic dysfunction is an important pathological hallmark and cause of Alzheimer's disease (AD). High-frequency stimulation (HFS)-induced long-term potentiation (LTP) has been widely used to study synaptic plasticity, with impaired LTP found to be associated with AD. However, the exact molecular mechanism underlying synaptic plasticity has yet to be completely elucidated. Whether genes regulating synaptic plasticity are altered in AD and contribute to disease onset also remains unclear. Herein, we induced LTP in the hippocampal CA1 region of wild-type (WT) and AD model mice by administering HFS to the CA3 region and then studied transcriptome changes in the CA1 region. We identified 89 genes that may participate in normal synaptic plasticity by screening HFS-induced differentially expressed genes (DEGs) in mice with normal LTP, and 43 genes that may contribute to synaptic dysfunction in AD by comparing HFS-induced DEGs in mice with normal LTP and AD mice with impaired LTP. We further refined the 43 genes down to 14 by screening for genes with altered expression in pathological-stage AD mice without HFS induction. Among them, we found that the expression of Pygm, which catabolizes glycogen, was also decreased in AD patients. We further demonstrated that down-regulation of PYGM in neurons impaired synaptic plasticity and cognition in WT mice, while its overexpression attenuated synaptic dysfunction and cognitive deficits in AD mice. Moreover, we showed that PYGM directly regulated energy generation in neurons. Our study not only indicates that PYGM-mediated energy production in neurons plays an important role in synaptic function, but also provides a novel LTP-based strategy to systematically identify genes regulating synaptic plasticity under physiological and pathological conditions.

Extensive studies indicate that β-amyloid (Aβ) aggregation is pivotal for Alzheimer's disease (AD) progression; however, cumulative evidence suggests that Aβ itself is not sufficient to trigger AD-associated degeneration, and whether other additional pathological factors drive AD pathogenesis remains unclear. Here, we characterize pathogenic aggregates composed of β2-microglobulin (β2M) and Aβ that trigger neurodegeneration in AD. β2M, a component of major histocompatibility complex class I (MHC class I), is upregulated in the brains of individuals with AD and constitutes the amyloid plaque core. Elevation of β2M aggravates amyloid pathology independent of MHC class I, and coaggregation with β2M is essential for Aβ neurotoxicity. B2m genetic ablation abrogates amyloid spreading and cognitive deficits in AD mice. Antisense oligonucleotide- or monoclonal antibody-mediated β2M depletion mitigates AD-associated neuropathology, and inhibition of β2M-Aβ coaggregation with a β2M-based blocking peptide ameliorates amyloid pathology and cognitive deficits in AD mice. Our findings identify β2M as an essential factor for Aβ neurotoxicity and a potential target for treating AD.

Orientin alleviates cognitive deficits and oxidative stress in Aβ1–42-induced mouse model of Alzheimer's disease

Impairment of Glycolysis-Derived l-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimer’s Disease

One of the earliest changes associated with Alzheimer's disease (AD) is the loss of catecholaminergic terminals in the cortex and hippocampus originating from the Locus Coeruleus (LC). This decline leads to reduced catecholaminergic neurotransmitters in the hippocampus, affecting synaptic plasticity and spatial memory. However, it is unclear whether restoring catecholaminergic transmission in the terminals from the LC may alleviate the spatial memory deficits associated with AD. This study aims to investigate the effects of optogenetic stimulation of LC catecholaminergic projections on alleviating spatial memory and synaptic plasticity deficits associated with AD. We conducted experiments using a 12-month-old 3xTgAD mouse model (AD-TH) that expresses Cre recombinase under the control of the tyrosine hydroxylase (TH) gene. This model enabled us to photostimulate the terminals from the LC in the hippocampal CA1 region before performing two different spatial memory tasks and inducing long-term plasticity. Optogenetic stimulation successfully reversed the impairment of spatial memory retrieval in aging AD-TH mice. Furthermore, this stimulation restored levels of catecholaminergic neurotransmitters in the hippocampus and enhanced synaptic plasticity, as demonstrated by a long-term potentiation (LTP) protocol. These findings suggest a critical role for the LC-hippocampal CA1 catecholaminergic circuitry in disrupting synaptic plasticity and the spatial memory deficits characteristic of the early stages of AD. The study highlights the potential for targeting LC catecholaminergic pathways as a therapeutic strategy to improve cognitive deficits experienced by AD patients.

Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer’s Disease

RAS-GRF1 is a guanine nucleotide exchange factor with the ability to activate RAS and RAC GTPases in response to elevated calcium levels. We previously showed that beginning at 1 month of age, RAS-GRF1 mediates NMDA-type glutamate receptor (NMDAR)-induction of long term depression in the CA1 region of the hippocampus of mice. Here we show that beginning at 2 months of age, when mice first acquire the ability to discriminate between closely related contexts, RAS-GRF1 begins to contribute to the induction of long term potentiation (LTP) in the CA1 hippocampus by mediating the action of calcium-permeable, AMPA-type glutamate receptors (CP-AMPARs). Surprisingly, LTP induction by CP-AMPARs through RAS-GRF1 occurs via activation of p38 MAP kinase rather than ERK MAP kinase, which has more frequently been linked to LTP. Moreover, contextual discrimination is blocked by knockdown of Ras-Grf1 expression specifically in the CA1 hippocampus, infusion of a p38 MAP kinase inhibitor into the CA1 hippocampus, or the injection of an inhibitor of CP-AMPARs. These findings implicate the CA1 hippocampus in the developmentally dependent capacity to distinguish closely related contexts through the appearance of a novel LTP-supporting signaling pathway.

Dysfunction of synaptic plasticity leads to memory impairment in Alzheimer's disease (AD). Muscone (Mus) has shown neuroprotective effects in cerebral ischemic models. However, little is known of Mus effects on AD. To investigate the effects of Mus on memory functions and synaptic plasticity in 6-month-old APP/PS1 double-transgenic mice and explore the potential mechanisms. Mus was intraperitoneally injected into APP/PS1 or wild-type mice, and cognitive function was assessed by Novel object recognition and Morris water maze tests. The levels of amyloid-β (Aβ) were evaluated by immunofluorescence staining and ELISA. Synaptic morphology and plasticity were evaluated by Golgi staining and long-term potentiation. Cell viability was examined by Cell Counting Kit-8 assay. The protein levels of histone deacetylase 2 (HDAC2) were accessed by western blotting and Immunofluorescence staining. The protein levels of microtubule associated protein 2 and synaptophysin were analyzed by immunofluorescence staining. The ubiquitination of HDAC2 was examined by co-immunoprecipitation. The interaction of Mus with HDAC2 was predicted by molecular docking analysis. Mus treatment attenuated memory dysfunction, reduced Aβ level, and enhanced synaptic plasticity in APP/PS1 mice. In addition, Mus treatment decreased the level of HDAC2 in the hippocampus of APP/PS1 mice and Aβ1-42-induced primary neurons, which might be associated with increased HDAC2 ubiquitination induced by HDAC2 and Mus interaction. Mus protected against synaptic plasticity and memory impairment in APP/PS1 mice, and enhanced HDAC2 degradation via ubiquitination, indicating that Mus was a potential drug for AD treatment.

Simple SummaryAs of the past decade, phytochemicals have become a major target of interest in cancer chemopreventive and chemotherapeutic research. Sulforaphane (SFN) is a metabolite of the phytochemical glucoraphanin, which is found in high abundance in cruciferous vegetables, such as broccoli, watercress, Brussels sprouts, and cabbage. In both distant and recent research, SFN has been shown to have a multitude of anticancer effects, increasing the need for a comprehensive review of the literature. In this review, we critically evaluate SFN as an anticancer agent and its mechanisms of action based on an impressive number of in vitro, in vivo, and clinical studies.There is substantial and promising evidence on the health benefits of consuming broccoli and other cruciferous vegetables. The most important compound in broccoli, glucoraphanin, is metabolized to SFN by the thioglucosidase enzyme myrosinase. SFN is the major mediator of the health benefits that have been recognized for broccoli consumption. SFN represents a phytochemical of high interest as it may be useful in preventing the occurrence and/or mitigating the progression of cancer. Although several prior publications provide an excellent overview of the effect of SFN in cancer, these reports represent narrative reviews that focused mainly on SFN’s source, biosynthesis, and mechanisms of action in modulating specific pathways involved in cancer without a comprehensive review of SFN’s role or value for prevention of various human malignancies. This review evaluates the most recent state of knowledge concerning SFN’s efficacy in preventing or reversing a variety of neoplasms. In this work, we have analyzed published reports based on in vitro, in vivo, and clinical studies to determine SFN’s potential as a chemopreventive agent. Furthermore, we have discussed the current limitations and challenges associated with SFN research and suggested future research directions before broccoli-derived products, especially SFN, can be used for human cancer prevention and intervention.

Thermodynamic and kinetic origins of Alzheimer's and related diseases: A chemical engineer's perspective

Abstract： Ministry of Health and Welfare (MOHW) recently released the top ten causes of death, cancer is still one of the top ten in Taiwan. So the cancer prevention and therapy is the most important now. In recent years, Researchers have found that natural plant materials or biologically active ingredients have strong chemo-preventive effects and may play a role of cancer treatment or therapeutic drugs. The Sulforaphane (SFN) is one of the isothiocyanate groupswithorganosulfur compounds which were from cruciferous vegetables such as broccoli or cabbages. It is produced when the myrosinase transforms glucoraphanin, a glucosinolate, to SFN upon damage to the plant, such as from chewing. This study investigated the anti-tumor activity of sulforaphane (SFN) in the human triple-negative breast cancer cell line, MDA-MB-231. Our results demonstrate the ability of SFN to induce cell cycle G2 / M arrest and inhibit cell growth. The activity of Cdc2 and Cyclin B1 expression at the G2 / M transition is an important factor in determining whether cell cycle arrest occurs before or during mitotic progression. The results of western blot analysis did not reveal significant inhibition of Cdc2; however, an increase in phosphorylation Cdc2Tyr15 expression was observed. Results show that SFN blocks cell mitosis via the inhibition of Cdc25c activity resulting in a decrease in Cdc2 dephosphorylation. This makes it possible for Cdc2 and Cyclin B1 complex to form the maturation-promoting factor (MPF). In this study, Co-Immunoprecipitation (Co-IP) was used to detect the Cdc2 / Cyclin B1 complex association. Our results revealed SFN-induced cell cycle G2 / M Phase delay through the inhibition of activity related to the Cdc2 / Cyclin B1 association. The results of Human cell cycle PCR array analysis revealed a significant increase in CDK5R1 and SERTAD1 gene expression following treatment with SFN. CDK5R1 has been linked to neuronal apoptosis, whereas SERTAD1 is an oncogene shown to promote the survival of various types of cancer cells through the inhibition of cell apoptosis.Western blot analysis revealed that treatment with SFN inhibits SERTAD1 expression and increases the expression of CDK5R1. This is a clear indication that the SFN-induced cell cycle G2 / M Phase delay may be associated with an increase in CDK5R1 and a decrease SERTAD1 expression. These results demonstrate the potential of SFN as an alternative route for the treatment and/or prevention of breast cancer.

Aims: Strong evidence has implicated synaptic failure as a direct contributor to cognitive decline in Alzheimer's disease (AD), and selenium (Se) supplementation has demonstrated potential for AD treatment. However, the exact roles of Se and related selenoproteins in mitigating synaptic deficits remain unclear. Results: Our data show that selenomethionine (Se-Met), as the major organic form of Se in vivo, structurally restored synapses, dendrites, and spines, leading to improved synaptic plasticity and cognitive function in triple transgenic AD (3 × Tg-AD) mice. Furthermore, we found that Se-Met ameliorated synaptic deficits by inhibiting extrasynaptic N-methyl-d-aspartate acid receptors (NMDARs) and stimulating synaptic NMDARs, thereby modulating calcium ion (Ca2+) influx. We observed that a decrease in selenoprotein K (SELENOK) levels was closely related to AD, and a similar disequilibrium was found between synaptic and extrasynaptic NMDARs in SELENOK knockout mice and AD mice. Se-Met treatment upregulated SELENOK levels and restored the balance between synaptic and extrasynaptic NMDAR expression in AD mice. Innovation: These findings establish a key signaling pathway linking SELENOK and NMDARs with synaptic plasticity regulated by Se-Met, and thereby provide insight into mechanisms by which Se compounds mediate synaptic deficits in AD. Conclusion: Our study demonstrates that Se-Met restores synaptic deficits through modulating Ca2+ influx mediated by synaptic and extrasynaptic NMDARs in 3 × Tg-AD mice, and suggests a potentially functional interaction between SELENOK and NMDARs. Antioxid. Redox Signal. 35, 863-884.

Optimized theranostic strategies for Alzheimer's disease (AD) remain almost absent from bench to clinic. Current probes and drugs attempting to prevent β‐amyloid (Aβ) fibrosis encounter failures due to the blood–brain barrier (BBB) penetration challenge and blind intervention time window. Herein, we design a near‐infrared (NIR) aggregation‐induced emission (AIE) probe, DNTPH, via balanced hydrophobicity‐hydrophilicity strategy. DNTPH binds selectively to Aβ fibrils with a high signal‐to‐noise ratio. In vivo imaging revealed its excellent BBB permeability and long‐term tracking ability with high‐performance AD diagnosis. Remarkably, DNTPH exhibits a strong inhibitory effect on Aβ fibrosis and promotes fibril disassembly, thereby attenuating Aβ‐induced neurotoxicity. DNTPH treatment significantly reduced Aβ plaques and rescued learning deficits in AD mice. Thus, DNTPH serves as the first AIE in vivo theranostic agent for real‐time NIR imaging of Aβ plaques and AD therapy simultaneously.

BackgroundExtensive evidence has indicated that a high rate of cholesterol biogenesis and abnormal neuronal energy metabolism play key roles in Alzheimer’s disease (AD) pathogenesis. Here, for the first time, we used protein and peptide, a plant protein homolog of mammalian adiponectin, to determine its therapeutic efficacy in different AD models.MethodMice were grouped before treatment as follows: WT and Transgenic mice (APP/PS1 and Adipo‐/‐ mice) were administered via intraperitoneal injection with 3 types of solution (saline, osmotin and osmotin mimetic peptide). Mice were decapitated at the age of 5, 9, 12 or 16 months. Protein samples were analyzed by immunobloting as well as immunofluorescence. Brain sections were analyzed by immune histochemistry. LTP was measured by mEPSC.ResultOsmotin, natural plant protein, and its mimetic peptide treatment modulated adiponectin receptor 1 (AdipoR1), significantly induced AMPK/SIRT1 activation, and reduced SREBP2 expression in both in vivo and in vitro AD and Adiponectin deficient mice. Osmotin acts Via AdipoR1/AMPK/SIRT1/SREBP2 and TNFR1 signaling pathway, Osmotin and its mimetic peptide significantly diminished amyloidogenic Aβ production, abundance and aggregation, accompanied by improved pre‐ and post‐synaptic dysfunction, cognitive impairment, memory deficits. Most importantly, it reversed the suppression of long‐term potentiation (LTP) in AD mice. Interestingly, AdipoR1, AMPK, and SIRT1 silencing not only abolished Osmotin capability but also further enhanced AD pathology by increasing SREBP2, APP, and β‐secretase (BACE1) expression and the levels of toxic Aβ production. Likewise, mimetic peptide mechanistically instigates AdipoR1/AMPK signaling and consequently suppressed the hyperactivated TNF‐α/TNFR1 signaling in both in vivo and in vitro models of AD.ConclusionOsmotin and its mimetic peptide mitigate aberrant brain‐energy metabolism and AD pathology in in vivo and in vitro AD models via regulating AdipoR1/AMPK/SIRT1/SREBP2/TNFR1 signaling pathway. These results suggest that Osmotin and peptide‐based mimetics can be a potential candidate for AD treatment.

Sulforaphane restores acetyl-histone H3 binding to Bcl-2 promoter and prevents apoptosis in ethanol-exposed neural crest cells and mouse embryos