Hippocampus Of Alzheimer's Disease Mice Research Articles

MiR-137-3p mechanisms of action and blood-brain barrier penetrating and neuron-targeting lipid nanoparticles deliver miR-137-3p for the treatment of Alzheimer's disease

IntroductionThis study aimed to investigate the impact of miR-137-3p on the pathogenesis of Alzheimer's disease (AD) and develop a pioneering in vivo delivery method for its therapeutic potential. MethodsThis study was initiated by quantifying the levels of miR-137-3p in both human neuroblastoma cells and a mouse model of AD. Our focus was on elucidating its effects on microtubule (MT) stability, tau protein hyperphosphorylation, synaptic damage, and other hallmark features of AD. To circumvent the risks associated with direct brain injections, a novel drug delivery system was engineered, employing lipid nanoparticles (LNPs) functionalized with rabies virus glycoprotein to facilitate the transcytosis of miR-137-3p across the blood-brain barrier and target its delivery directly to neurons. ResultsThe results confirmed miR-137-3p deficiency in both AD cells and animal models. A protective effect of miR-137-3p on MT stability in the AD model was first observed in SH-SY5Y. We validated that the delivery system could effectively penetrate the blood-brain barrier and target neurons, resulting in a significant increase in miR-137-3p levels in the hippocampus of APP/PS1 mice. Glycogen synthase kinase-3 beta expression in the hippocampus of AD mice was inhibited, suggesting successful treatment of AD in this animal model. DiscussionThis study verified a new mechanism of action of miR-137-3p in AD pathogenesis in cells. By developing an LNPs-based miR-137-3p delivery system, this study offers a novel avenue for treating AD, highlighting miR-137-3p as a key factor in AD pathogenesis and its therapeutic application.

Pongamol Alleviates Neuroinflammation and Promotes Autophagy in Alzheimer's Disease by Regulating the Akt/mTOR Signaling Pathway.

Alzheimer's disease (AD), one of the neurodegenerative disorders, is highly correlated with the abnormal hyperphosphorylation of Tau and aggregation of β-amyloid (Aβ). Oxidative stress, neuroinflammation, and abnormal autophagy are key drivers of AD and how they contribute to neuropathology remains largely unknown. The flavonoid compound pongamol is reported to possess a variety of pharmacological activities, such as antioxidant, antibacterial, and anti-inflammatory. This study investigated the neuroprotective effect and its mechanisms of pongamol in lipopolysaccharide (LPS)-induced BV2 cells, d-galactose/sodium nitrite/aluminum chloride (d-gal/NaNO2/AlCl3)-induced AD mice, and Caenorhabditis elegans models. Our research revealed that pongamol reduced the release of inflammatory factors IL-1β, TNF-α, COX-2, and iNOS in LPS-induced BV2 cells. Pongamol also protected neurons and significantly restored memory function, inhibited Tau phosphorylation, downregulated Aβ aggregation, and increased oxidoreductase activity in the hippocampus of AD mice. In addition, pongamol reversed the nuclear transfer of NF-κB and increased the levels of Beclin 1 and LC3 II/LC3 I. Most importantly, the anti-inflammatory and promoter autophagy effects of pongamol may be related to the regulation of the Akt/mTOR signaling pathway. In summary, these results showed that pongamol has a potential neuroprotective effect, which greatly enriched the research on the pharmacological activity of pongamol for improving AD.

Activity-based NIR specific fluorescent probe reveals the abnormal elevation of prolyl endopeptidase in hippocampus during Alzheimer's disease progression

Although prolyl endopeptidase (PREP) has become one of the important proteins to investigate the pathogenesis of Alzheimer's Disease (AD), the activity of PREP in the brain of AD patients is still controversial. This study aims to construct a novel enzyme-activated near-infrared (NIR) fluorescence probe for in-situ detection and imaging of PREP in brain, as well as to reveal the relationship between the activity variation of PREP and the development of AD. For these purposes, based on PREP's unique endopeptidase activity catalyzing prolyl-bond hydrolysis and cleavage, four probes deriving from a good NIR fluorophore (ACM) were designed and synthesized. Observations indicated that the Z-GP-ACM exhibited superior selectivity and sensitivity in detecting PREP. In addition, molecular thermodynamic/kinetic calculations and enzymatic kinetics studies also showed that Z-GP-ACM was an excellent substrate for PREP. Subsequent experiments demonstrated that Z-GP-ACM can be used to measure and image endogenous PREP in living cells and mouse brain. We also revealed for the first time that PREP activity was abnormally increased in hippocampus of AD mice during the disease progression. All these results highlighted that Z-GP-ACM could be a promising tool for exploring the biological functions of endogenous PREP in living systems.

Antagonizing LINGO-1 reduces activated microglia and alleviates dendritic spine loss in the hippocampus of APP/PS1 transgenic mice

In Alzheimer's disease (AD), microglia are involved in synaptic pruning and mediate synapse loss. LINGO-1 is a negative regulator of nerve growth, and whether antagonizing LINGO-1 can attenuate synaptic pruning by microglia and rescue dendritic spines in the hippocampus in AD is still unclear. On this basis, the anti-LINGO-1 antibody, which binds to LINGO-1 protein and antagonizes the effects of LINGO-1, was administered to 10-month-old APP/PS1 transgenic mice for 2 months. The Morris water maze test, immunohistochemical and stereological methods, immunofluorescence and 3D reconstruction were used. Compared to wild-type mice, APP/PS1 transgenic mice had worse performance on behavioral tests, fewer dendritic spines but more microglia in the hippocampus. Meanwhile, the microglia in APP/PS1 transgenic mice had more branches of medium length (4–6 µm) and a cell body area with greater variability. Moreover, APP/PS1 transgenic mice had more postsynaptic termini colocalized with microglia in the hippocampus than wild-type mice. The anti-LINGO-1 antibody significantly reversed these changes in AD, indicating that the anti-LINGO-1 antibody can improve hippocampus-dependent learning and memory abilities and effectively rescue dendritic spines in the hippocampus of AD mice and that microglia might participate in this progression in AD. These results provide a scientific basis for further studying the mechanism of the anti-LINGO-1 antibody in AD and help to elucidate the role of LINGO-1 in the treatment of AD.

Noise exposure increase apoptosis in the hippocampus of AD mice through the upregulation of CTSS

In recent years, it has become an acknowledged fact that noise exposure can lead to cognitive impairments, and researchers have shown increasing interest in this area. However, the detrimental impact of noise exposure on Alzheimer's disease (AD) animal models might be considerably greater than on ordinary model mice, yet the mechanisms by which noise exposure affects the hippocampus in these models have been scarcely investigated. This study we used 4D Label-free proteomics to identify distinctive differentially expressed proteins in the hippocampus of AD model mice following noise exposure. Among these proteins, the presence of Cathepsin S(CTSS) cannot be disregarded. Utilizing experimental techniques such as Western blot, immunofluorescence, and rt-qPCR, we confirmed the expression of CTSS in the hippocampus of APP/PS1 mice after noise exposure. Additionally, we examined downstream molecules including P53,BCL-2, BAX, and CASPASE3 using KEGG pathway analysis. The results indicated an elevation in CTSS expression, a reduction in the anti-apoptotic gene BCL-2, and an increase in the expression of BAX and cleaved CASPASE3. Based on these findings, we hypothesize that noise exposure potentially heightens apoptosis within the hippocampus through upregulating CTSS expression, subsequently posing a threat to AD model animals.

Impact of Donepezil Supplementation on Alzheimer's Disease-like Pathology and Gut Microbiome in APP/PS1 Mice.

Based on published information, the occurrence and development of Alzheimer's disease (AD) are potentially related to gut microbiota changes. Donepezil hydrochloride (DH), which enhances cholinergic activity by blocking acetylcholinesterase (AChE), is one of the first-line drugs for AD treatment approved by the Food and Drug Administration (FDA) of the USA. However, the potential link between the effects of DH on the pathophysiological processes of AD and the gut microbiota remains unclear. In this study, pathological changes in the brain and colon, the activities of superoxide dismutase (SOD) and AChE, and changes in intestinal flora were observed. The results showed that Aβ deposition in the prefrontal cortex and hippocampus of AD mice was significantly decreased, while colonic inflammation was significantly alleviated by DH treatment. Concomitantly, SOD activity was significantly improved, while AChE was significantly reduced after DH administration. In addition, the gut microbiota community composition of AD mice was significantly altered after DH treatment. The relative abundance of Akkermansia in the AD group was 54.8% higher than that in the N group. The relative abundance of Akkermansia was increased by 18.3% and 53.8% in the AD_G group and the N_G group, respectively. Interestingly, Akkermansia showed a potential predictive value and might be a biomarker for AD. Molecular docking revealed the binding mode and major forces between DH and membrane proteins of Akkermansia. The overall results suggest a novel therapeutic mechanism for treating AD and highlight the critical role of gut microbiota in AD pathology.

The bexarotene derivative OAB-14 ameliorates cognitive decline in APP/PS1 transgenic mice by suppressing microglia-mediated neuroinflammation through the PPAR-γ pathway

Neuroinflammation is believed to be a critical process involved in the pathophysiology of Alzheimer's disease (AD). In this study, we investigated the pharmacological ability of OAB-14, a small molecule compound derived from bexarotene, to reduce neuroinflammation and improve cognitive decline in an AD mouse model (in vivo) and its ability to regulate signaling pathways implicated in neuroinflammation in vitro. It was found that OAB-14 significantly improved the cognitive function of 11-month-old AD mice (APP/PS1 transgenic mice) in a dose-dependent manner. Simultaneously, OAB-14 dramatically inhibited the activation of microglia in the cerebral cortex and hippocampus of AD mice and dose-dependently downregulated the expression of nuclear factor kappa B (NF-κB) and NOD-like receptor protein 3 (NLRP3) in the cerebral cortex. At the cellular level, OAB-14 reversed the downregulation of M2 phenotypic markers, including mannose receptor C-type 1 (MRC1) and arginase 1 (ARG1), in lipopolysaccharide (LPS)- or amyloid-β protein oligomer (oAβ1-42)-activated BV2 microglial cells and partially restored their ability to clear Aβ. However, these effects were suppressed when peroxisome proliferator-activated receptor-γ (PPAR-γ) was specifically inhibited by GW9662, a selective PPAR-γ antagonist. These results suggested that OAB-14 could regulate microglial polarization by regulating PPAR-γ signaling, thereby mitigating neuroinflammation and improving cognitive function in AD mice.

Integrating Network Pharmacology and Component Analysis to Study the Potential Mechanisms of Qi-Fu-Yin Decoction in Treating Alzheimer's Disease.

To elucidate the potential mechanisms of QFY for the treatment of Alzheimer's Disease (AD), and explore the effective substances of QFY. UPLC-LTQ-Orbitrap-MS was used to identify the chemical constituents of the serum samples and the cerebrospinal fluid samples of rats after QFY administration. Network pharmacology was used to predict potential targets and pathways of QFY against AD. The AD mice model was established by subcutaneous injection of D-gal for 8 consecutive weeks. New object recognition (NOR) and Morris water maze test (MWM) were used to evaluate the learning and memory abilities of mice. Moreover, the levels of TNF-α, IL-1β, and IL-18 in the brain hippocampus of mice were determined by ELISA. The expression of Bax, Bcl-2, Caspase-1, PSD95, SYP, ICAM-1 and MCP-1 proteins in the hippocampus was detected by Western blotting. Furthermore, qRT-PCR was used to detect the gene expressions of PSD95, SYP, M1 and M2 polarization markers of microglia, including iNOS, CD16, ARG-1, and IL-10 in the hippocampus. A total of 51 prototype compounds were detected in rat serum and 15 prototype components were identified in rat cerebrospinal fluid. Behavioral experiments revealed that QFY significantly increased the recognition index, decreased the escape latency, increased the platform crossing times and increased the residence time in the target quadrant. QFY also could alleviate the ultrastructural pathological changes in the hippocampus of AD mice. Meanwhile, QFY treatment suppressed the expression of inflammatory factors, such as TNF-α, IL-1β, and IL-18. QFY improved the synaptic plasticity of the hippocampus in D-gal model mice by significantly increasing the expression of proteins and mRNAs of PSD95 and SYP. QFY could effectively improve the learning and memory impairment of D-gal-induced AD mice by inhibiting the excessive activation of microglia, enhancing the expression of M2 microglia, inhibiting the increase of inflammatory factors, cell adhesion factors and chemokines, anti-apoptosis, and improving synaptic plasticity.

Hippocampal Reduction of α-Synuclein via RNA Interference Improves Neuropathology in Alzheimer's Disease Mice.

Alzheimer's disease (AD) cases are often characterized by the pathological accumulation of α-synuclein (α-syn) in addition to amyloid-β (Aβ) and tau hallmarks. The role of α-syn has been extensively studied in synucleinopathy disorders, but less so in AD. Recent studies have shown that α-syn may also play a role in AD and its downregulation may be protective against the toxic effects of Aβ accumulation. We hypothesized that selectively knocking down α-syn via RNA interference improves the neuropathological and biochemical findings in AD mice. Here we used amyloid precursor protein transgenic (APP-Tg) mice to model AD and explore pathologic and behavioral phenotypes with knockdown of α-syn using RNA interference. We selectively reduced α-syn levels by stereotaxic bilateral injection of either LV-shRNA α-syn or LV-shRNA-luc (control) into the hippocampus of AD mice. We found that downregulation of α-syn results in significant reduction in the number of Aβ plaques. In addition, mice treated with LV-shRNA α-syn had amelioration of abnormal microglial activation (Iba1) and astrocytosis (GFAP) phenotypes in AD mice. Our data suggests a novel link between Aβ and α-syn pathology as well as a new therapeutic angle for targeting AD.

Wwl70-induced ABHD6 inhibition attenuates memory deficits and pathological phenotypes in APPswe/PS1dE9 mice

Synaptic dysfunction plays a crucial role in the pathogenesis of Alzheimer's disease (AD). α/β-hydrolase domain-containing 6 (ABHD6) contributes to synaptic dysfunctions, and ABHD6 inhibition has shown potential therapeutic value in neurological disorders. However, the role of ABHD6 in AD has not been fully defined. In this study, we demonstrated that adeno-associated virus (AAV) mediated shRNA targeting ABHD6 in hippocampal neurons attenuated synaptic dysfunction and memory impairment of APPswe/PS1dE9 (APP/PS1) mice, while it didn't affect the amyloid-beta (Aβ) levels and neuroinflammation in the brains. In addition, intraperitoneal injection of wwl70, a specific inhibitor of ABHD6, improved synaptic plasticity and memory function in APP/PS1 mice, which might attribute to the activation of endogenous cannabinoid signaling. Furthermore, wwl70 significantly decreased the Aβ levels and neuroinflammation in the hippocampus of AD mice, and enhanced Aβ phagocytized by microglia. In conclusion, for the first time our data have shown that ABHD6 inhibition might be a promising strategy for AD treatment, and wwl70 is a potential candidate for AD drug development pipeline.

Dual Efficacy of a Catalytic Anti-Oligomeric Aβ42 scFv Antibody in Clearing Aβ42 Aggregates and Reducing Aβ Burden in the Brains of Alzheimer's Disease Mice.

One of the primary pathological mechanisms underlying Alzheimer's disease (AD) is the deposition of amyloid β-protein (Aβ42) aggregates in the brain. In this study, a catalytic anti-oligomeric Aβ42 scFv antibody, HS72, was identified by screening a human antibody library, its ability to degrade Aβ42 aggregates was defined, and its role in the reduction of Aβ burden in the AD mouse brain was evaluated. HS72 specifically targeted Aβ42 aggregates with an approximately 14-68kDa range. Based on molecular docking simulations, HS72 likely catalyzed the hydrolytic cleavage of the His13-His14 bond of Aβ42 chains in an Aβ42 aggregate unit, releasing N/C-terminal fragments and Aβ42 monomers. Degradation of Aβ42 aggregates by HS72 triggered a considerable disassembly or breakdown of the Aβ42 aggregates and greatly reduced their neurotoxicity. Aβ deposit/plaque load in the hippocampus of AD mice was reduced by approximately 27% after 7 days (once daily) of intravenous HS72 administration, while brain neural cells were greatly restored and their morphology was drastically improved. The above efficacies of HS72 were all greater than those of HT7, a simple anti-oligomeric Aβ42 scFv antibody. Although a catalytic anti-oligomeric Aβ42 antibody may have a slightly lower affinity for Aβ42 aggregates than a simple anti-oligomeric Aβ42 antibody, the former may display a stronger overall efficacy (dual efficacy of induction and catalysis) than the latter (induction alone) in clearing Aβ42 aggregates and improving histopathological changes in AD brain. Our findings on the catalytic antibody HS72 indicate the possibility of functional evolution of anti-oligomeric Aβ42 antibodies and provide novel insights into the immunotherapy of AD.

Age-Associated UBE2O Reduction Promotes Neuronal Death in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease leading to dementia in the elderly. Ubiquitin proteasome system (UPS) is critical for protein homeostasis, while the functional decline of UPS with age contributes to the pathogenesis of AD. Ubiquitin-conjugating enzyme E2O (UBE2O), an E2-E3 hybrid enzyme, is a major component of UPS. However, its role in AD pathogenesis has not been fully defined. We aimed to identify the age-associated expression of UBE2O and its role AD pathogenesis. Western blot analysis were used to assess expression of UBE2O in organs/tissues and cell lines. Immunofluorescence staining was performed to examine the cellular distribution of UBE2O. Neuronal death was determined by the activity of lactate dehydrogenase. UBE2O is highly expressed in the cortex and hippocampus. It is predominantly expressed in neurons but not in glial cells. The peak expression of UBE2O is at postnatal day 17 and 14 in the cortex and hippocampus, respectively. Moreover its expression is gradually reduced with age. Importantly, UBE2O is significantly reduced in both cortex and hippocampus of AD mice. Consistently, overexpression of amyloid-β protein precursor (AβPP) with a pathogenic mutation (AβPPswe) for AD reduces the expression of UBE2O and promotes neuronal death, while increased expression of UBE2O rescues AβPPswe-induced neuronal death. Our study indicates that age-associated reduction of UBE2O may facilitates neuronal death in AD, while increasing UBE2O expression or activity may be a potential approach for AD treatment by inhibiting neuronal death.

Upregulation of Wnt2b exerts neuroprotective effect by alleviating mitochondrial dysfunction in Alzheimer's disease.

This study investigated the relationship between plasma Wnt2b levels and Alzheimer's disease (AD), and explored the effect of Wnt2b on mitochondrial dysfunction in AD. Healthy and AD subjects, AD transgenic mice, and in vitro models were used to investigate the roles of Wnt2b in abnormalities in canonical Wnt signaling and mitochondria in AD. RT-qPCR, immunoblotting, and immunofluorescence analysis were performed to assay canonical Wnt signaling. Mitochondrial structure was analyzed by electron microscopy. Flow cytometry was used to examine the intracellular calcium and neuronal apoptosis. Plasma Wnt2b levels were lower in AD patients and positively correlated with cognitive performance. Similarly, Wnt2b was reduced in the hippocampus of AD mice and in vitro models. Next, Wnt2b overexpression and recombinant Wnt2b were used to endogenously and exogenously upregulate Wnt2b levels. Upregulation of Wnt2b could effectively prevent downregulation of canonical Wnt signaling, mitochondrial dysfunction in in vitro AD models. Subsequently, intracellular calcium overload and neuronal damage were ameliorated. Our study highlights that Wnt2b decline is associated with cognitive impairment in AD, and upregulation of Wnt2b can exert neuroprotective effects in AD, particularly in ameliorating mitochondrial dysfunction.

Protective effect of pterostilbene in a streptozotocin-induced mouse model of Alzheimer's disease by targeting monoamine oxidase B.

Alzheimer's disease (AD) is a neurodegenerative disease in elderly population. Pterostilbene (PTS) is a resveratrol analog with neuroprotective activity. However, the biological mechanisms of PTS in AD progression are largely uncertain. An animal model of AD was established using streptozotocin (STZ)-treated C57BL/6J mice. Monoamine oxidase B (MAOB) expression was analyzed by bioinformatics analysis and detected by western blotting assay. The memory impairment was investigated by Morris water maze test. The levels of Tau hyperphosphorylation and death-related proteins were detected by western blotting analysis. The levels of amyloid β (Aβ)1-42 accumulation, oxidative stress-related markers (ROS, MDA, SOD, and GSH), and inflammation-relative markers (TNF-α, IL-1β, IL-6, and p-NF-κB) were measured by ELISA. MAOB expression was increased in hippocampus of AD mice, and it was decreased by PTS. PTS attenuated STZ-induced body weight loss and memory impairment by regulating MAOB. PTS mitigated Aβ1-42 accumulation and Tau hyperphosphorylation by regulating MAOB in STZ-treated mice. PTS attenuated neuronal death by decreasing cleaved caspase-3 and Bax levels and increasing Bcl2 expression in hippocampus by regulating MAOB in STZ-treated mice. PTS weakened STZ-induced oxidative stress in hippocampus by decreasing ROS and MDA levels and increasing SOD and GSH levels by regulating MAOB. PTS protected against STZ-induced neuroinflammation in hippocampus by inhibiting TNF-α, IL-1β, IL-6, and p-NF-κB levels through regulating MAOB. In conclusion, PTS alleviates STZ-induced memory impairment, Aβ1-42 accumulation, Tau hyperphosphorylation, neuronal death, oxidative stress, and inflammation by decreasing MAOB in AD mice, proving anti-AD potential of PTS.

Anti-LINGO-1 antibody treatment alleviates cognitive deficits and promotes maturation of oligodendrocytes in the hippocampus of APP/PS1 mice.

Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1), a negative regulator of oligodendrocyte differentiation and myelination, is associated with cognitive function, and its expression is highly upregulated in Alzheimer's disease (AD) patients. Anti-LINGO-1 antibody treatment can effectively antagonize the negative regulatory effect of LINGO-1. In this study, we aim to assess the effect of anti-LINGO-1 antibody treatment on cognition and hippocampal oligodendrocytes in an AD transgenic animal model. First, 10-month-old male amyloid-β (Aβ) protein precursor (APP)/presenilin 1 (PS1) mice were administered anti-LINGO-1 antibody for 8weeks. Then, learning and memory abilities were assessed with the Morris water maze (MWM) and Y-maze tests, and Aβ deposition and hippocampal oligodendrocytes were investigated by immunohistochemistry, immunofluorescence, and stereology. We found that anti-LINGO-1 antibody alleviated the deficits in spatial learning and memory abilities and working and reference memory abilities, decreased the density of LINGO-1 positive cells, decreased Aβ deposition, significantly increased the number of mature oligodendrocytes and the density of myelin, reversed the abnormal increases in the number of oligodendrocyte lineage cells and the densities of oligodendrocytes precursor cells in APP/PS1 mice. Our results provide evidence that LINGO-1 might be involved in the process of oligodendrocyte dysmaturity in the hippocampus of AD mice, and that antagonizing LINGO-1 can alleviate cognitive deficits in APP/PS1 mice and decrease Aβ deposition and promote oligodendrocyte differentiation and maturation in the hippocampus of these mice. Our findings suggest that changes in LINGO-1 and oligodendrocytes in the hippocampus play important roles in the pathogenesis of AD and that antagonizing LINGO-1 might be a potential therapeutic strategy for AD.

Protective effects of hydroxy-α-sanshool from the pericarp of Zanthoxylum bungeanum Maxim. On D-galactose/AlCl3-induced Alzheimer's disease-like mice via Nrf2/HO-1 signaling pathways

Hydroxy-α-sanshool (HAS) is an unsaturated fatty acid amide from Zanthoxylum bungeanum Maxim. with hypolipidemic, hypoglycemic, anti-inflammatory, and neurotrophic effects, etc. In this study, results indicated that HAS effectively ameliorated spontaneous locomotion deficit of mice induced by D-galactose (D-gal) and AlCl3 treatment in open field test. Results of Morris water maze test (MWM) showed that HAS significantly improved the spatial learning and memory ability of aging mice. Histopathological evaluations revealed that HAS markedly alleviated morphological changes and increased number of Nissl neurons in hippocampus of D-gal/AlCl3-induced Alzheimer's disease (AD)-like mice. HAS markedly reduced malondialdehyde (MDA) production, and increased the activity of antioxidative enzymes including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), showing an inhibitory effect on oxidative stress. Furthermore, HAS treatment obviously reversed the inhibitory expressions of mRNA and protein of HO-1 and Nrf2 in the hippocampus of AD mice, suggesting that neuroprotective effects of HAS against oxidative stress might be mediated by the Nrf2/HO-1 pathway. Meanwhile, HAS significantly inhibited neuronal apoptosis by decreasing mRNA and protein expressions of Cyt-c, Bax and Caspase 3, and increasing Bcl-2 expression in the hippocampus of AD mice. These results suggest that HAS have the potential to be developed as antioxidant drug for the prevention and early therapy of AD.

Binding to Amyloid‐β Protein by Photothermal Blood‐Brain Barrier‐Penetrating Nanoparticles for Inhibition and Disaggregation of Fibrillation

AbstractExcess accumulation of amyloid‐β (Aβ) protein in the brain is the primary pathogenesis of Alzheimer's disease (AD). Inhibition of Aβ fibrillation and disaggregation of Aβ fibrils is an attractive therapeutic and preventive strategy for Aβ‐induced AD. Here, near infrared (NIR) light‐responsive nanoparticles (NPs) composed of amphiphilic guanidinocalix[5]arene (GC5A), 4‐(dodecyloxy)benzamido‐terminated methoxy poly(ethylene glycol), and photothermal conjugated polymer PDPP are fabricated. The NIR light‐responsive NPs can efficiently penetrate the blood‐brain barrier (BBB), inhibit amyloid‐β 42 (Aβ42) fibrillation, and disaggregate fibrils after NIR light irradiation. Through the advantage of containing GC5A, the NPs exhibit extremely strong binding affinity for the Aβ42 protein. Interestingly, upon NIR light irradiation, benefiting from the high photothermal conversion efficiency of PDPP, NPs generate local heat and effectively promote the BBB permeability. Moreover, NPs are multifunctional platforms for the inhibition of Aβ42 fibrillation and disaggregation of fibrils after irradiation with NIR light, distinctly reducing cytotoxicity and eliminating Aβ42 plaques in the hippocampus of AD mice. Hence, NPs provide an interesting strategy for the inhibition and disaggregation of Aβ42 fibrillation and present an excellent therapeutic strategy for amyloidosis.

Anti-LINGO-1 antibody ameliorates cognitive impairment, promotes adult hippocampal neurogenesis, and increases the abundance of CB1R-rich CCK-GABAergic interneurons in AD mice

In view of the negative regulatory effect of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) on neurons, an antibody against LINGO-1 (anti-LINGO-1 antibody) was herein administered to 10-month-old APP/PS1 transgenic Alzheimer's disease (AD) mice for 2 months as an experimental intervention. Behavioral, stereology, immunohistochemistry and immunofluorescence analyses revealed that the anti-LINGO-1 antibody significantly improved the cognitive abilities, promoted adult hippocampal neurogenesis (AHN), decreased the amyloid beta (Aβ) deposition, enlarged the hippocampal volume, and increased the numbers of total neurons and GABAergic interneurons, including GABAergic and CCK-GABAergic interneurons rich in cannabinoid type 1 receptor (CB1R), in the hippocampus of AD mice. In contrast, this intervention significantly reduced the number of GABAergic interneurons expressing LINGO-1 and CB1R in the hippocampus of AD mice. More importantly, we also found a negative correlation between LINGO-1 and CB1R on GABAergic interneurons in the hippocampus of AD mice, while the anti-LINGO-1 antibody reversed this relationship. These results indicated that LINGO-1 plays an important role in the process of hippocampal neuron loss in AD mice and that antagonizing LINGO-1 can effectively prevent hippocampal neuron loss and promote AHN. The improvement in cognitive abilities may be attributed to the improvement in AHN, and in the numbers of GABAergic interneurons and CCK-GABAergic interneurons rich in CB1Rs in the hippocampus of AD mice induced by the anti-LINGO-1 antibody. Collectively, the double target effect (LINGO-1 and CB1R) initiated by the anti-LINGO-1 antibody may provide an important basis for the study of drugs for the prevention and treatment of AD in the future.

Schisandrin Inhibits NLRP1 Inflammasome-Mediated Neuronal Pyroptosis in Mouse Models of Alzheimer's Disease.

BackgroundIn recent years, schisandrin (SCH) was proved to improve Alzheimer's Disease (AD). The aim of our study is to explore the effect of SCH on neuronal pyroptosis in the disease.MethodsA Morris water maze test was performed to evaluate the spatial learning and memory retention of AD mouse. ELISA was fulfilled to examine the concentration of Aβ, IL-1β, and IL-18. Western blot was performed to detect the expression of apoptosis- and pyroptosis-related proteins. Besides, the neuronal apoptosis rate was examined using TUNEL assay. Immunohistochemistry was utilized to detect the activation of NLRP1 inflammasome.ResultsHere, AD mice have serious cognitive impairment. Meantime, Aβ was highly expressed in the brains of AD mice. SCH could effectively rescue the cognitive impairment in AD mice and impede the production of Aβ. Subsequently, we further demonstrated that SCH repressed neuronal apoptosis, pyroptosis-related proteins expression, and the activation of NLRP1 inflammasome in the hippocampus of AD mice. We also proved that Aβ induced neuronal apoptosis and pyroptosis in vitro. However, the effects of Aβ on neuronal apoptosis and pyroptosis were partly reversed by SCH treatment.ConclusionOverall, our data indicated that SCH improved cognitive impairment in AD mice through inhibition of NLRP1 inflammasome-mediated neuronal pyroptosis and neuronal apoptosis. Our works provided new evidence to support SCH acting as a potential treatment method in AD.

A study on inhibition of the Aβ1-42-induced inflammatory response by the Huatuo Zaizao pill through the NF-κB signaling pathway.

The pathology of Alzheimer's disease (AD) includes β-amyloid (Aβ) (plaques) and neurofibrillary tangles (NFTs). This study aimed to explore the efficacy of Huatuo Zaizao pill (HTZP) in an AD mouse model induced by injecting Aβ1-42, and the neuroprotective mechanism of HTZP in AD. C57BL/6 (B6) mice were randomly divided into 4 groups (n = 10, per group): control group, AD model group, and 2 different doses of HTZP treated groups. The Morris water maze test was carried out on AD mice to assess the learning ability after treatment with HTZP for 15 day. The levels of inflammatory factors and the nuclear factor-κB (NF-κB) pathway were examined by western blot and real-time polymerase chain reaction (PCR). The content of microglia was investigated by immunofluorescence. This study revealed that a cognitive disorder could be mitigated when the AD mice were treated with HTZP, which might be associated with the decreased level of pro-inflammatory factors, and the inhibitory activities of microglia. Additionally, phosphorylation of IκB and NF-κB p65 could be reduced by prohibiting the neuroinflammation of NF-κB activation in the hippocampus of AD mice. These results showed that HTZP could mitigate a cognitive disorder, diminish the activation of microglia, and inhibit the content of inflammatory factors through the NF-κB pathway in Aβ1-42-induced AD mice. HTZP may be an appropriate agent for AD treatment in the future.