Reduced Aβ Deposition Research Articles

Phyllodulcin improves hippocampal long-term potentiation in 5XFAD mice

Alzheimer's disease (AD) is a well-known neurodegenerative brain disease, and no curative treatment has yet been developed. The main symptoms include various brain lesions, caused by amyloid β (Aβ) aggregation, and cognitive decline. Therefore, it is believed that substances that control Aβ will inhibit the onset of Alzheimer's disease and slow its progression. In this study, the effect of phyllodulcin, a major component of hydrangea, on Aβ aggregation and brain pathology in an animal model of AD was studied. Phyllodulcin inhibited the aggregation of Aβ and decomposed the pre-aggregated Aβ in a concentration-dependent manner. In addition, it inhibited the cytotoxicity of Aβ aggregates. Oral administration of phyllodulcin improved Aβ-induced memory impairments in normal mice, reduced Aβ deposition in the hippocampus, inhibited the activation of microglia and astrocytes, and improved synaptic plasticity in 5XFAD mice. These results suggest that phyllodulcin may be a candidate for the treatment of AD.

Aerial part of Houttuynia cordata reverses memory impairment by regulating amyloid beta accumulation and neuroinflammation in Alzheimer's disease model.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by amyloid-β (Aβ) deposition, accompanied by neuroinflammation and memory dysfunction. Houttuyniae Herba (aerial parts of Houttuynia cordata, also known as fish mint; HH), an herbal medicine traditionally used to treat fever, urinary disorders, and pus, is revealed to protect neurons from Aβ toxicity and regulate cholinergic dysfunction in AD models. In this study, we aimed to investigate the effects of HH on excessive accumulation of Aβ followed by neuroinflammation, synaptic degeneration, and memory impairment. Two-month-old 5xFAD transgenic mice were administered HH at 100 mg/kg for 4months. We observed that HH treatment ameliorated memory impairment and reduced Aβ deposits in the brains of the mice. HH directly inhibited Aβ aggregation in vitro using the Thioflavin T assay and indirectly suppressed the amyloidogenic pathway by increasing alpha-secretase expression in the mice brain. In addition, HH exerted antineuroinflammatory effects by reducing of glial activation and p38 phosphorylation. Moreover, HH treatment increased the expression of synaptophysin, a presynaptic marker protein. Overall, HH alleviates memory impairment in AD by facilitating nonamyloidogenic pathway and inhibiting neuroinflammation. Therefore, we suggest that HH can be a promising herbal drug for patients with AD requiring multifaceted improvement.

Early activation of Toll-like receptor-3 reduces the pathological progression of Alzheimer’s disease in APP/PS1 mouse

BackgroundToll-like receptor 3 (TLR3) plays an important role in the immune/inflammatory response in the nervous system and is a main pathological feature of Alzheimer’s disease (AD). This study investigates the role of early activation of TLR3 in the pathophysiological process of AD.MethodsIn the experiment, the agonist of TLR3, Poly(I:C), was intraperitoneally injected into the APP/PS1 mouse model of AD and wild-type control mice starting from the age of 4 to 9 months. At the age of 14 months, behavioral tests were conducted. Western blot and immunohistochemistry staining were used to evaluate the level of amyloid β-protein (Aβ), the activation of inflammatory cells, and neuron loss. In addition, the levels of inflammatory cytokines were measured using a quantitative polymerase chain reaction.ResultsThe results demonstrated that the early activation of TLR3 attenuated neuronal loss and neurobehavioral dysfunction. Moreover, the early activation of TLR3 reduced Aβ deposition, inhibited the activation of microglia and astrocytes, and decreased the transcription of pro-inflammatory factors in the hippocampus.ConclusionsThe results indicated that the activation of TLR3 by Poly (I:C) in the early stage of development of AD in a mouse model attenuated neuron loss and improved neurobehavioral functions. The underlying mechanisms could be attributed to its role in Aβ clearance, the inhibition of glial cells, and the regulation of neuroinflammation in the hippocampus.

Trpc6 knockout improves behavioral dysfunction and reduces Aβ production by inhibiting CN-NFAT1 signaling in T2DM mice

As the prevalence of diabetes and health awareness increase, type 2 diabetes mellitus -associated cognitive dysfunction is receiving increasing attention. However, the pathogenesis is not entirely understood. Transient receptor potential cation channel 6 (TRPC6) is highly correlated with intracellular Ca2+ concentrations, and neuronal calcium overload is an important cause of cognitive dysfunction. In the present study, we investigated the effect and mechanism of Trpc6 knockout in high-fat diet and streptozotocin-induced T2DM mice. The body weight and fasting blood glucose were recorded during the experiment. Behavioral dysfunction was detected using the open field test (OFT), elevated plus maze (EPM), hole-board test (HBT), Morris water maze (MWM) test and contextual fear conditioning (CFC) test. Nissl and H&E staining were used to examine neuronal damage. Western blot, quantitative real-time polymerase chain reaction (q-PCR), and immunofluorescence were performed to detect amyloid beta protein (Aβ) deposition and related indicators of neurological impairments in the cerebral cortex and hippocampus. The results indicated that Trpc6 knockout inhibited body weight loss and fasting blood glucose increase, improved spontaneous activity, learning and memory dysfunction, and alleviated neuroinflammation and neuronal damage in T2DM mice. The further results demonstrated that Trpc6 knockout decreased Aβ generation and deposition, and reduced the expressions of inflammasome-related proteins in T2DM mice. In addition, Trpc6 knockout inhibited intracellular calcium overload in diabetic mice and primary cultured hippocampal neurons, which in turn suppressed CN and NFAT1 expression. These data suggest that Trpc6 knockout may inhibit the CN-NFAT1 signaling pathway by decreasing intracellular calcium overload in the brain of T2DM mice, which consequently reduce Aβ deposition and neuroinflammation, and ultimately delay the development of T2DM-associated cognitive dysfunction.

Hederagenin improves Alzheimer's disease through PPARα/TFEB-mediated autophagy

BackgroundAutophagic flux is coordinated by a network of master regulatory genes, which centered on transcription factor EB (TFEB). The disorders of autophagic flux are closely associated with Alzheimer's disease (AD), and thus restoring autophagic flux to degrade pathogenic proteins has become a hot therapeutic strategy. Hederagenin (HD), a triterpene compound, isolated from a variety food such as Matoa (Pometia pinnata) Fruit, Medicago sativa, Medicago polymorpha L. Previous studies have shown that HD has the neuroprotective effect. However, the effect of HD on AD and underlying mechanisms are unclear. PurposeTo determine the effect of HD on AD and whether it promotes autophagy to reduce AD symptoms. Study DesignBV2 cells, C. elegans and APP/PS1 transgenic mice were used to explore the alleviative effect of HD on AD and the molecular mechanism in vivo and in vitro. MethodsThe APP/PS1 transgenic mice at 10 months were randomized into 5 groups (n = 10 in each group) and orally administrated with either vehicle (0.5% CMCNa), WY14643 (10 mg/kg/d), low-dose of HD (25 mg/kg/d), high-dose of HD (50 mg/kg/d) or MK-886 (10 mg/kg/d) + HD (50 mg/kg/d) for consecutive 2 months. The behavioral experiments including morris water maze test, object recognition test and Y maze test were performed. The effects of HD on Aβ deposition and alleviates Aβ pathology in transgenic C. elegans were operated using paralysis assay and fluorescence staining assay. The roles of HD in promoting PPARα/TFEB-dependent autophagy were investigated using the BV2 cells via western blot analysis, real-time quantitative PCR (RT-qPCR), molecular docking, molecular dynamic (MD) simulation, electron microscope assay and immunofluorescence. ResultsIn this study, we found that HD upregulated mRNA and protein level of TFEB and increased the distribution of TFEB in the nucleus, and the expressions of its target genes. HD also promoted the expressions of LC3BII/LC3BI, LAMP2, etc., and promoted autophagy and the degradation of Aβ. HD reduced Aβ deposition in the head area of C. elegans and Aβ-induced paralysis. HD improved cognitive impairment and pathological changes in APP/PS1 mice by promoting autophagy and activating TFEB. And our results also showed that HD could strongly target PPARα. More importantly, these effects were reversed by treatment of MK-886, a selective PPARα antagonist. ConclusionOur present findings demonstrated that HD attenuated the pathology of AD through inducing autophagy and the underlying mechanism associated with PPARα/TFEB pathway.

Combined with UPLC-Triple-TOF/MS-based plasma lipidomics and molecular pharmacology reveals the mechanisms of schisandrin against Alzheimer’s disease

BackgroundAlzheimer’s disease (AD), a type of neurodegeneration disease, is characterized by Aβ deposition and tangles of nerve fibers. Schisandrin is one of the main components of Fructus Schisandrae Chinensis. Researches showed that schisandrin can improve the cognitive impairment and memory of AD mice, but the specific mechanism has not been fully elucidated.PurposeThe purpose of this study is to investigate the possible mechanism of schisandrin in improving AD pathology.MethodsThe Morris water maze test was executed to detect spatial learning and memory. Ultra performance liquid chromatography-Triple time of flight mass spectrometry (UPLC-Triple-TOF/MS)-based plasma lipidomics was used to study the changes of plasma lipids. Moreover, we measured the levels of protein and mRNA expression of APOE and ABCA1 in the rat brains and in BV2 microglia.ResultsOur study found that schisandrin could improve learning and memory, and reduce Aβ deposition in AD rats. Furthermore, we found that schisandrin can improve plasma lipid metabolism disorders. Therefore, we hypothesized schisandrin might act via LXR and the docking results showed that schisandrin interacts with LXRβ. Further, we found schisandrin increased the protein and mRNA expression of LXR target genes APOE and ABCA1 in the brain of AD rats and in BV2 microglia.ConclusionOur study reveals the neuroprotective effect and mechanism of schisandrin improves AD pathology by activating LXR to produce APOE and ABCA1.

An NIR-Driven Upconversion/C3N4/CoP Photocatalyst for Efficient Hydrogen Production by Inhibiting Electron-Hole Pair Recombination for Alzheimer's Disease Therapy.

Redox imbalance and abnormal amyloid protein (Aβ) buildup are key factors in the etiology of Alzheimer's disease (AD). As an antioxidant, the hydrogen molecule (H2) has the potential to cure AD by specifically scavenging highly harmful reactive oxygen species (ROS) such as •OH. However, due to the low solubility of H2 (1.6 ppm), the traditional H2 administration pathway cannot easily achieve long-term and effective accumulation of H2 in the foci. Therefore, how to achieve the continuous release of H2 in situ is the key to improve the therapeutic effect on AD. As a corollary, we designed a rare earth ion doped g-C3N4 upconversion photocatalyst, which can respond to NIR and realize the continuous production of H2 by photocatalytic decomposition of H2O in biological tissue, which avoids the problem of the poor penetration of visible light. The introduction of CoP cocatalyst accelerates the separation and transfer of photogenerated electrons in g-C3N4, thus improving the photocatalytic activity of hydrogen evolution reaction. The morphology of the composite photocatalyst was shown by transmission electron microscopy, and the crystal structure was studied by X-ray diffractometry and Raman analysis. In addition, the ability of g-C3N4 to chelate metal ions and the photothermal properties of CoP can inhibit Aβ and reduce the deposition of Aβ in the brain. Efficient in situ hydrogen production therapy combined with multitarget synergism solves the problem of a poor therapeutic effect of a single target. In vivo studies have shown that UCNP@CoP@g-C3N4 can reduce Aβ deposition, improve memory impairment, and reduce neuroinflammation in AD mice.

Imine-Linked Covalent Organic Framework Modulates Oxidative Stress in Alzheimer’s Disease

Oxidative stress due to Cu2+-triggered aggregation of β-amyloid protein (Aβ) and reactive oxygen species (ROS) overexpression in the brain is an important hallmark of early stages of Alzheimer's disease (AD) pathogenesis. The ideal modulator for improving the oxidative stress microenvironment in AD brains should take both Cu2+ and ROS into consideration, which has been rarely reported. Here, a combined therapeutic strategy was achieved by co-encapsulating superoxide dismutase (SOD) and catalase (CAT) in imine-linked covalent organic frameworks (COFs), which were modified with peptide KLVFF (T5). The nanocomposite SC@COF-T5 exhibited an oxidative stress eradicating ability through ROS elimination and Cu2+ chelation, combined with the inhibition of Aβ42 monomer aggregation and disaggregation of Aβ42 fibrils. In vivo experiments indicated that SC@COF-T5 with a high blood-brain barrier (BBB) penetration efficiency was effective to reduce Aβ deposition, expression of pro-inflammatory cytokines, ROS levels, and neurologic damage in AD model mice, consequently rescuing memory deficits of AD mice. This work not only confirms the feasibility and merits of the therapeutic strategy regarding multiple targets for treatment of early AD pathogenesis but also opens up a novel direction for imine-linked COFs in biomedical applications.

Humulus lupulus L. Extract Protects against Senior Osteoporosis through Inhibiting Amyloid β Deposition and Oxidative Stress in APP/PS1 Mutated Transgenic Mice and Osteoblasts

As aging progresses, β-amyloid (Aβ) deposition and the resulting oxidative damage are key causes of aging diseases such as senior osteoporosis (SOP). Humulus lupulus L. (hops) is an important medicinal plant widely used in the food, beverage and pharmaceutical industries due to its strong antioxidant ability. In this study, APP/PS1 mutated transgenic mice and Aβ-injured osteoblasts were used to evaluate the protective effects of hops extracts (HLE) on SOP. Mice learning and memory levels were assessed by the Morris water maze. Mice femurs were prepared for bone micro-structures and immunohistochemistry experiments. The deposition of Aβ in the hippocampus, cortex and femurs were determined by Congo red staining. Moreover, protein expressions related to antioxidant pathways were evaluated by Western blotting. It was found that HLE markedly improved learning abilities and ameliorated memory impairment of APP/PS1 mice, as well as regulated antioxidant enzymes and bone metabolism proteins in mice serum. Micro-CT tests indicated that HLE enhanced BMD and improved micro-architectural parameters of mice femur. More importantly, it was discovered that HLE significantly reduced Aβ deposition both in the brain and femur. Further in vitro results showed HLE increased the bone mineralization nodule and reduced the ROS level of Aβ-injured osteoblasts. Additionally, HLE increased the expression of antioxidant related proteins Nrf2, HO-1, NQO1, FoxO1 and SOD-2. These results indicated that Humulus lupulus L. extract could protect against senior osteoporosis through inhibiting Aβ deposition and oxidative stress, which provides a reference for the clinical application of hops in the prevention and treatment of SOP.

Breviscapine Combined with BMSCs Reduces Aβ Deposition in Rat with Alzheimer's Disease by Regulating Circular RNA ciRS-7.

This study aimed to clarify that breviscapine combined with bone marrow mesenchymal stem cells (BMSCs) treatment can reduce Aβ deposition in Alzheimer's disease (AD) patients. AD is a common degenerative disease of the central nervous system. Aβ protein deposition in the cerebral cortex and hippocampus causes neuronal peroxidation damage, synaptic dysfunction, neuroinflammation, and nerve cell apoptosis, and ultimately leads to AD. To investigate whether breviscapine combined with BMSCs treatment can reduce Aβ deposition in AD. The AD rat model was successfully induced by Aβ1-42. The expression of protein and mRNA was detected by western blot and reverse transcription-quantitative PCR (RT-qPCR), respectively. In AD rat brain tissue, the expression of circular RNA ciRS-7 (ciRS-7), ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), and NF-kappaB p65 was significantly downregulated, and the expression of β-amyloid precursor protein (APP), β-site APPcleaving enzyme 1 (BAEC1), and Aβ was upregulated. The expression of ciRS-7, UCHL1, and p65 was significantly upregulated after breviscapine or BMSCs treatment, and there was increased APP and BAEC1 degradation. Notably, breviscapine combined with BMSCs treatment was more effective than either treatment alone. In SH-SY5Y cells, overexpression of ciRS-7 reduced Aβ deposition by upregulating UCHL1 to degrade APP and BAEC1, but these effects were reversed with inhibition of NF-kB signaling. Finally, knockdown of ciRS-7 elevated Aβ, APP, and BAEC1 expression in each group of rats compared with the control. Breviscapine combined with BMSCs treatment can reduce Aβ deposition in AD rats and promote the degradation of APP and BAEC1 by activating NF-kB to promote UCHL1 expression.

Sulforaphene, a CDK5 Inhibitor, attenuates cognitive deficits in a transgenic mouse model of Alzheimer's disease via reducing Aβ Deposition, tau hyperphosphorylation and synaptic dysfunction.

Alzheimer's disease (AD) is the most common form of neurodegenerative disorder characterized by progressive loss of memory and cognitive functions. There are two pathological hallmarks, including accumulation of amyloid plaques composed of β-amyloid peptide (Aβ) and deposits of neurofibrillatory tangles (NFT). Cyclin-dependent kinase 5 (CDK5), a serine/threonine kinase, plays an important role in synaptic plasticity and cognitive behavior. Sulforaphene (SF) has been demonstrated to exert anti-AD activity in AD rat model. In this study, we aimed to evaluate the cognitive deficits improving effects of SF on in TgCRND8 mice and to elucidate the underlying molecular mechanisms. TgCRND8 mice were intragastrically treated with SF (25 and 50mg/kg) for 4months from 3-month-old. The cognitive functions were assessed using Morris Water Maze Test. Cultured primary mouse neurons were pre-treated with SF, followed by co-treatment with Aβ1-42 oligomers. CDK5 inhibitor (roscovitine) was used to determine the involvement of CDK5/p25 pathway in the anti-AD effects of SF in primary neurons. Our results showed that SF treatment significantly ameliorated the cognitive deficits in TgCRND8 mice and protected primary mouse neurons against Aβ1-42 induced neurotoxicity. SF could modulate the expression of Aβ production related markers, and suppress the phosphorylation of tau protein at specific sites in the TgCRND8 mice. In addition, SF enhanced the expressions of synaptic plasticity related markers and CDK5. SF also markedly suppressed the CDK5/p25 activity. SF is a potent CDK5 inhibitor and a potential therapeutic agent for treatment and prevention of AD. Moreover, SF inhibited the overexpression of CDK5 in primary neurons of mouse.

An integrated study on the comprehensive mechanism of Schisandra chinensis polysaccharides mitigating Alzheimer's disease in rats using a UPLC-Q-TOF-MS based serum and urine metabolomics strategy.

As a well-known traditional Chinese medicine and functional food, Schisandra chinensis (S. chinensis) has been proved to possess excellent neuroprotective effects, and particularly the role of the polysaccharide fraction in neuroprotection has been increasingly emphasized. The aim of this study was to investigate the therapeutic effects and potential mechanism of action of the homogeneous polysaccharide SCP2, isolated and purified from S. chinensis polysaccharide (SCP), on Alzheimer's disease (AD) rats based on a holistic metabolomics approach in serum and urine. The results of the pharmacodynamics study showed that SCP2 significantly improved Aβ25-35-induced cognitive dysfunction, improved oxidative damage and reduced Aβ deposition in the hippocampus. The holistic metabolomics results of serum and urine showed that the intervention with SCP2 significantly reversed the metabolic profile disorder in AD rats. A total of 40 metabolites (21 serum metabolites and 19 urine metabolites) were identified, which were mainly involved in linoleic acid metabolism, alpha-linolenic acid metabolism and arachidonic acid metabolism. The results obtained in this study will provide new insights into the mechanisms of SCP2 in the treatment of AD and provide a basis for the subsequent structure-activity studies of SCP2.

Versatile lipoprotein-inspired nanocomposites rescue Alzheimer's cognitive dysfunction by promoting Aβ degradation and lessening oxidative stress.

The accumulation of amyloid-β (Aβ) into senile plaques and the resulting continuous oxidative stress are major pathogenic mechanisms in Alzheimer's disease (AD). In this study, we designed a lipoprotein-inspired nanoparticle to facilitate Aβ clearance and alleviate oxidative stress for the treatment of AD. Lipoprotein-like nanocomposites (RLA-rHDL@ANG) were fabricated by assembling reconstituted high density lipoprotein (rHDL) with an apoE-derived peptide (RLA) with Aβ binding and clearance capabilities, and were subsequently camouflaged using reactive oxygen species (ROS)-sensitive DSPE-TK-mPEG2000 and DSPE-TK-PEG3400-ANG with brain penetration as well as ROS scavenging ability. Immunoelectron microscopy, fluorescence colocalization, and enzyme linked immunosorbent assay, together with a thioflavin-T (ThT) fluorescence quantitative test, showed that RLA-rHDL@ANG possessed the ability of high binding affinity to both Aβ monomers and oligomers, and disintegration of pre-formed Aβ aggregates. ROS level monitoring and transmission electron microscopy (TEM) showed that RLA-rHDL@ANG possessed ROS sensitivity and consumption properties. Transcellular assay and in vivo imaging showed that RLA-rHDL@ANG effectively facilitated blood-brain barrier (BBB) penetration and intracerebral accumulation. It promoted the efficient degradation of Aβ by microglia and neurons through lysosomal transport and elimination approaches. Four-week administration of RLA-rHDL@ANG effectively reduced Aβ deposition, decreased the ROS level and improved cognitive functions in AD mice. These findings indicate that multifunctional RLA-rHDL@ANG may serve as a promising and feasible candidate for managing the progression of AD.

Fruquintinib/HMPL-013 ameliorates cognitive impairments and pathology in a mouse model of cerebral amyloid angiopathy (CAA)

Cerebral amyloid angiopathy (CAA) is characterized by the cerebrovascular amyloid-β (Aβ) accumulation, and always accompanied by Alzheimer's disease (AD). The mechanisms revealing CAA pathogenesis are still unclear, and it is challenging to develop an efficient therapeutic strategy for its treatment. Vascular endothelial growth factor (VEGF) and its receptors including VEGFR-1,-2,-3 activation are involved in Aβ processing, and modulate numerous cellular events associated with central nervous system (CNS) diseases. In the present study, we attempted to explore the regulatory function of fruquintinib (also named as HMPL-013), a highly selective inhibitor of VEGFR-1,-2,-3 tyrosine kinases, on CAA progression in Tg-SwDI mice. Here, we found that HMPL-013-rich diet consumption for 12 months significantly improved the behavioral performances and cerebral blood flow (CBF) of Tg-SwDI mice compared with the vehicle group. Importantly, HMPL-013 administration considerably reduced Aβ1-40 and Aβ1-42 burden in cortex and hippocampus of Tg-SwDI mice through regulating Aβ metabolism process. Congo red staining confirmed Aβ deposition in vessel walls, reflecting CAA formation, which was, however, strongly ameliorated after HMPL-013 treatment. Neuron death, aberrant glial activation and pro-inflammatory response in brain tissues of Tg-SwDI mice were dramatically alleviated after HMPL-013 consumption. More studies showed that the protective effects of HMPL-013 against CAA might be partially attributed to its regulation on the expression of genes associated with blood vasculature. Intriguingly, VEGF and phosphorylated VEGFR-1,-2 protein expression levels were remarkably decreased by HMPL-013 in cortex and hippocampus of Tg-SwDI mice, which were validated in HMPL-013-treated brain vascular endothelial cells (BVECs) under hypoxia. Finally, we found that VEGF-induced human umbilical vein endothelial cells (HUVEC) proliferation and tube formation were strongly abolished upon HMPL-013 exposure. Collectively, all these findings demonstrated that oral administration of HMPL-013 had therapeutic potential against CAA by reducing Aβ deposition, inflammation and neuron death via suppressing VEGF/VEGFR-1,-2 signaling.

Mechanisms Mediating the Anti‐inflammatory Effects of Eicosapentaenoic Acid in the APPswePS1dE9 Alzheimer's Mouse Model

AbstractBackgroundAlzheimer’s disease (AD) is a progressive, neurodegenerative disorder characterized by amyloid‐beta (Aβ) plaques, which may be exacerbated by obesity. We previously reported anti‐obesity and anti‐inflammatory effects of eicosapentaenoic acid (EPA), in diet‐induced obese mice. Therefore, the objective of this research is to determine whether EPA also protects against AD‐associated Aβ deposition.MethodMale and female AD mouse model APPswePS1E9 transgenic (TG) and non‐TG wild type littermates (WT) were fed with low fat (LF), high fat (HF), or HF supplemented with 36g/kg EPA (EPA) for 8 months. Mice were metabolically phenotyped during the intervention and blood and tissues were collected at the end of the study. Cortex RNA was isolated, and changes in genes related to AD, obesity, and inflammation were measured. Data were analyzed by 3‐way ANOVA using GraphPad Prism.ResultHF groups weighed significantly more than LF groups (p < 0.001), but other groups were comparable regardless of diet or genotype but overall, males weighed more than females. TG mice had higher serum Aβ‐40 levels than WT mice (p= 0.004), paralleled with higher cortex human APP mRNA levels in TG mice (p = 0.0204). Compared to HF, EPA decreased serum Aβ‐40 in WT male mice (p = 0.0182) as well as APP gene expression in the cortex of male and female TG mice (p = 0.0168 and 0.0030). Moreover, TG mice expressed higher level of MCP1 and IL1β (p = 0.0158 and 0.0142, respectively) mRNA levels compared to WT. Females in both genotypes expressed higher level of MCP1, IL1β and NLRP3 than males (p = 0.0025, 0.0038, and < 0.0001 respectively). In addition, EPA exhibited anti‐inflammatory effects in both sexes of TG mice as indicated by downregulation of mRNAs levels for MCP1 (p = 0.0226 and 0.0108) NLRP3 (p = 0.0205 and < 0.0001) and for IL1β in TG females only (p= 0.0344).ConclusionOur data indicate protective effects of EPA in AD, in part, by reducing Aβ deposition, possibly through inflammatory/neuroinflammatory mechanisms. Given the popularity of fish oil supplements, our findings merit further investigation to dissect mechanisms of fish oil effects especially in AD patients with obesity.

VX-765 Alleviates β-Amyloid Deposition and Secondary Degeneration in the Ipsilateral Hippocampus and Ameliorates Cognitive Decline after Focal Cortical Infarction in Rats

Focal cortical infarction leads to secondary degeneration of the ipsilateral hippocampus, which is associated with poststroke cognitive impairment. VX-765 is a potent small-molecule caspase-1 inhibitor that protects against central nervous system diseases. The present study aimed to determine the protective effects of VX-765 on β-amyloid (Aβ) deposition and secondary degeneration in the hippocampus as well as cognitive decline after cortical infarction. Sprague–Dawley rats were used to establish a distal middle cerebral artery occlusion (dMCAO) model and randomly divided into the vehicle and VX-765 groups. Rats in the vehicle and VX-765 groups, respectively, were subcutaneously injected with VX-765 (50 mg/kg/d) and an isopycnic vehicle once a day for 28 days, starting 1 h after dMCAO. At the end of this 28-day period, cognitive impairment was evaluated with the Morris water maze, and secondary hippocampal damage was evaluated with Nissl staining and immunostaining methods. Neuronal damage and pyroptosis were detected by TUNEL and immunoblotting. The results revealed that VX-765 treatment ameliorated poststroke cognitive dysfunction after ischemia. VX-765 reduced Aβ deposition, neuronal loss, and glial activation compared with the vehicle control. In addition, VX-765 treatment increased BDNF levels and normalized synaptophysin protein levels in the hippocampus after cortical infarction. Notably, VX-765 treatment significantly reduced the expression of the pyroptosis-related molecules caspase-1, NLRP3, apoptosis-associated speck-like protein (ASC), gasdermin D, IL-1β, and IL-18. Additionally, VX-765 significantly decreased the numbers of TUNEL-positive cells and the levels of Bax and cleaved caspase-3 (cC3) and enhanced the levels of Bcl-2 and Bcl-xl after ischemia. Inflammatory pathways, such as the NF-κB and mitogen-activated protein kinase (MAPK) pathways, were inhibited by VX-765 treatment after ischemia. These findings revealed that VX-765 reduced Aβ deposition, pyroptosis, and apoptosis in the ipsilateral hippocampus, which may be associated with reduced secondary degeneration and cognitive decline following focal cortical infarction.

Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae

Brain Aβ deposition is a key early event in the pathogenesis of Alzheimer´s disease (AD), but the long presymptomatic phase and poor correlation between Aβ deposition and clinical symptoms remain puzzling. To elucidate the dependency of downstream pathologies on Aβ, we analyzed the trajectories of cerebral Aβ accumulation, Aβ seeding activity, and neurofilament light chain (NfL) in the CSF (a biomarker of neurodegeneration) in Aβ-precursor protein transgenic mice. We find that Aβ deposition increases linearly until it reaches an apparent plateau at a late age, while Aβ seeding activity increases more rapidly and reaches a plateau earlier, coinciding with the onset of a robust increase of CSF NfL. Short-term inhibition of Aβ generation in amyloid-laden mice reduced Aβ deposition and associated glial changes, but failed to reduce Aβ seeding activity, and CSF NfL continued to increase although at a slower pace. When short-term or long-term inhibition of Aβ generation was started at pre-amyloid stages, CSF NfL did not increase despite some Aβ deposition, microglial activation, and robust brain Aβ seeding activity. A dissociation of Aβ load and CSF NfL trajectories was also found in familial AD, consistent with the view that Aβ aggregation is not kinetically coupled to neurotoxicity. Rather, neurodegeneration starts when Aβ seeding activity is saturated and before Aβ deposition reaches critical (half-maximal) levels, a phenomenon reminiscent of the two pathogenic phases in prion disease.

Ginsenoside Rg1 alleviates learning and memory impairments and Aβ disposition through inhibiting NLRP1 inflammasome and autophagy dysfunction in APP/PS1 mice.

Alzheimer's disease (AD) is a common neurodegenerative disorder. Amyloid β (Aβ) deposition is considered an important pathological feature of AD. Growing evidence has linked neuroinflammation and autophagy to Aβ deposition in the progression of AD. However, there are few drug options for inhibiting neuroinflammation and autophagy to prevent AD. Ginsenoside Rg1 (Rg1), a steroidal saponin extracted from ginseng, has been reported to possess multiple neuroprotective effects. The present study aimed to evaluate whether Rg1 treatment could attenuate cognitive disorders and neuronal injuries by inhibiting NLRP1 inflammasome and autophagy dysfunction in an AD model of APP/PS1 mice. The results of behavioral tests indicated that Rg1 treatment for 12 weeks could significantly improve olfactory dysfunction as well as learning and memory impairments. The results of histopathological tests indicated that Rg1 treatment could reduce Aβ deposition and neuronal damages in APP/PS1‑9M mice. Additionally, the results of immunoblot, reverse transcription‑quantitative PCR or immunohistochemistry demonstrated that Rg1 treatment significantly downregulated the expression levels of inflammation‑related proteins of NLRP1, caspase1, IL‑1β and TNF‑α, as well as autophagy‑related proteins of p‑AMPK/AMPK, Beclin1 and LC3 II/LC3 I, and increased the expression levels of p‑mTOR/mTOR and P62 in APP/PS1‑9M mice. In addition, the molecular docking analysis showed that there was favorable binding result between Rg1 and NLRP1. The present study suggested that Rg1 may alleviate learning and memory impairments and Aβ disposition by inhibiting NLRP1 inflammasome and improving autophagy dysfunction, suggesting that Rg1 may be a potential therapeutic agent for delaying AD.

Association of low meal frequency with decreased in vivo Alzheimer’s pathology

Little is known about the association between meal frequency and Alzheimer's disease (AD) in humans. We tested the hypothesis that low meal frequency (LMF) is associated with reduced invivo AD pathology in human brain, and additionally investigated the mediation of serum ghrelin, a hunger-related hormone, for the association. A total of 411 non-demented older adults were systematically interviewed to identify their dietary patterns including meal frequency and underwent multi-modal neuroimaging for cerebral beta-amyloid (Aβ) and tau deposition, glucose metabolism, and cerebrovascular injury. LMF (less than three meals a day) was significantly associated with lower Aβ deposition compared to high meal frequency (HMF). In addition, both LMF and reduced Aβ deposition were significantly related to elevated serum ghrelin. Our findings suggest that LMF may be related to the lower risk of AD through reduced brain amyloid deposition. Additionally, ghrelin appears mediate the association between LMF and lower amyloid deposition.

Targeted brain delivery of RVG29-modified rifampicin-loaded nanoparticles for Alzheimer's disease treatment and diagnosis.

Alzheimer's disease (AD) is an aging‐related neurodegenerative disease. The main pathological features of AD are β‐amyloid protein (Aβ) deposition and tau protein hyperphosphorylation. Currently, there are no effective drugs for the etiological treatment of AD. Rifampicin (RIF) is a semi‐synthetic broad‐spectrum antibiotic with anti‐β‐amyloid deposition, anti‐inflammatory, anti‐apoptosis, and neuroprotective effects, but its application in AD treatment has been limited for its strong hydrophobicity, high toxicity, short half‐life, low bioavailability, and blood–brain barrier hindrance. We designed a novel brain‐targeted and MRI‐characteristic nanomedicine via loading rabies virus protein 29 (RVG29), rifampicin, and Gd on poly (l‐lactide) nanoparticles (RIF@PLA‐PEG‐Gd/Mal‐RVG29). The cytotoxicity assay demonstrated that RIF@PLA‐PEG‐Gd/Mal‐RVG29 had favorable biocompatibility and security. Fluorescence imaging in vivo showed that PLA‐PEG‐Gd/Mal‐RVG29 could deliver rifampicin into the brain by enhancing cellular uptake and brain targeting performance, leading to improvement of the bioavailability of rifampicin. In in vivo study, RIF@PLA‐PEG‐Gd/Mal‐RVG29 improved the spatial learning and memory capability of APP/PS1 mice in the Morris water maze, as compared to rifampicin. Immunofluorescence, TEM, immunoblotting, and H&E staining revealed that RIF@PLA‐PEG‐Gd/Mal‐RVG29 reduced Aβ deposition in hippocampal and cortex of APP/PS1 mice, improved the damage of synaptic ultrastructure, increased the expression level of PSD95 and SYP, as well as reduced the necrosis of neurons. These findings suggest that RIF@PLA‐PEG‐Gd/Mal‐RVG29 may be an effective strategy for the treatment of AD.