Activation of the heat shock response as a therapeutic strategy for tau toxicity.

Alzheimer's disease is associated with the misfolding and aggregation of two distinct proteins, beta-amyloid and tau. Previously, it has been shown that activation of the cytoprotective heat shock response (HSR) pathway reduces beta-amyloid toxicity. Here, we show that activation of the HSR is also protective against tau toxicity in a cell-autonomous manner. Overexpression of HSF-1, the master regulator of the HSR, ameliorates the motility defect and increases the lifespan of transgenic C. elegans expressing human tau. By contrast, RNA interference of HSF-1 exacerbates the motility defect and shortens lifespan. Targeting regulators of the HSR also affects tau toxicity. Additionally, two small-molecule activators of the HSR, Geranylgeranylacetone (GGA) and Arimoclomol (AC), have substantial beneficial effects. Taken together, this research expands the therapeutic potential of HSR manipulation to tauopathies and reveals that the HSR can impact both beta-amyloid and tau proteotoxicity in Alzheimer's disease.

Microglia either promote or restrain TRAIL-mediated excitotoxicity caused by Aß1-42 oligomers.

BACKGROUND: Alzheimer's disease (AD) features progressive neurodegeneration and microglial activation that results in dementia and cognitive decline. The release of soluble amyloid (Aß) oligomers into the extracellular space is an early feature of AD pathology. This can promote excitotoxicity and microglial activation. Microglia can adopt several activation states with various functional outcomes. Protective microglial activation states have been identified in response to Aß plaque pathology in vivo. However, the role of microglia and immune mediators in neurotoxicity induced by soluble Aß oligomers is unclear. Further, there remains a need to identify druggable molecular targets that promote protective microglial states to slow or prevent the progression of AD. METHODS: Hippocampal entorhinal brain slice culture (HEBSC) was employed to study mechanisms of Aß1-42 oligomer-induced neurotoxicity as well as the role of microglia. The roles of glutamate hyperexcitation and immune signaling in Aß-induced neurotoxicity were assessed using MK801 and neutralizing antibodies to the TNF-related apoptosis-inducing ligand (TRAIL) respectively. Microglial activation state was manipulated using Gi-hM4di designer receptor exclusively activated by designer drugs (DREADDs), microglial depletion with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX3397, and microglial repopulation (PLX3397 withdrawal). Proteomic changes were assessed by LC-MS/MS in microglia isolated from control, repopulated, or Aß-treated HEBSCs. RESULTS: Neurotoxicity induced by soluble Aß1-42 oligomers involves glutamatergic hyperexcitation caused by the proinflammatory mediator and death receptor ligand TRAIL. Microglia were found to have the ability to both promote and restrain Aß-induced toxicity. Induction of microglial Gi-signaling with hM4di to prevent pro-inflammatory activation blunted Aß neurotoxicity, while microglial depletion with CSF1R antagonism worsened neurotoxicity caused by Aß as well as TRAIL. HEBSCs with repopulated microglia, however, showed a near complete resistance to Aß-induced neurotoxicity. Comparison of microglial proteomes revealed that repopulated microglia have a baseline anti-inflammatory and trophic phenotype with a predicted pathway activation that is nearly opposite that of Aß-exposed microglia. mTORC2 and IRF7 were identified as potential targets for intervention. CONCLUSION: Microglia are key mediators of both protection and neurodegeneration in response to Aß. Polarizing microglia toward a protective state could be used as a preventative strategy against Aß-induced neurotoxicity.

Small Molecule Decoy of Amyloid-ß Aggregation Blocks Activation of Microglia-Like Cells.

Background: Aggregated forms of the amyloid-ß (Aß) peptides which form protofibrils and fibrils in the brain are signatures of Alzheimer's disease (AD). Aggregates are also recognized by microglia, which in early phases may be protective and in later phases contribute to the pathology. We have identified several small molecules, decoys which interfere with Aß oligomerization and induce other aggregation trajectories leading to aggregated macrostructures which are non-toxic. Objective: This study investigates whether the small-molecule decoys affect microglial activation in terms of cytokine secretion and phagocytosis of Aß peptide. Methods: The effects of the decoys (NSC 69318, NSC 100873, NSC 16224) were analyzed in a model of human THP-1 monocytes differentiated to microglia-like cells. The cells were activated by Aß40 and Aß42 peptides, respectively, and after treatment with each decoy the secreted levels of pro-inflammatory cytokines and the Aß phagocytosis were analyzed. Results: NSC16224, which generates a double-stranded aggregate of thin protofibrils, was found to block Aß40- and Aß42-induced increase in microglial secretion of pro-inflammatory cytokines. NSC 69318, selective for neurotoxicity of Aß42, and NSC 100873 did not significantly reduce the microglial activation in terms of cytokine secretion. The uptake of Aß42 was not affected by anyone of the decoys. Conclusions: Our findings open the possibility that the molecular decoys of Aß aggregation may block microglial activation by Aß40 and Aß42 in addition to blocking neurotoxicity as shown previously.

Near-infrared laser diode mitigates Aß1-42-induced neurodegeneration in cortical neurons.

Alzheimer's disease, a prevalent neurodegenerative condition primarily affecting older adults, remains incurable. Its principle pathological hallmark is the accelerated accumulation of amyloid ß (Aß) protein. This study investigates the potential of photobiomodulation using near infrared light to counteract Aß1-42-induced synaptic degeneration and neurotoxicity. We focused on the effect of 808 nm near-infrared laser diode (LD) on Aß1-42 cytotoxicity in primary cultured cortical neurons. We assessed cell survival using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, observing substantial benefits from LD irradiation with a power of 10 mW and a dose of 30 J. Cells exposed to Aß1-42 exhibited morphological changes indicative of synaptic damage and a significant decrease in the number of postsynaptic density protein-95 (PSD-95) contacts, which were significantly improved with near-infrared LD therapy. Furthermore, this therapy reduced Aß and phosphorylated tau (P-tau) protein accumulation. Additionally, near-infrared LD irradiation substantially lessened the Aß1-42-induced rise in glial fibrillary acid protein (GFAP) and ionized calcium-binding adaptor molecule 1 (IBA1) in astrocytes and microglia. Remarkably, near-infrared LD irradiation effectively inhibited phosphorylation of key proteins involved in Aß1-42-induced necroptosis, namely Receptor-interacting protein kinase-3 (RIP3) and Mixed Lineage Kinase domain-Like protein (MLKL). Our findings suggest that near-infrared LD treatment significantly reduces neurodegeneration by reducing glial overactivation and neuronal necroptosis triggered by Aß1-42. Thus, near-infrared LD treatment emerges as a promising approach for slowing or treating Alzheimer's disease, offering new avenues in its management.

Aß25-35-induced autophagy and apoptosis are prevented by the CRMP2-derived peptide ST2-104 (R9-CBD3) via a CaMKKß/AMPK/mTOR signaling hub.

We previously reported that the peptide ST2-104 (CBD3, for Ca2+ channel-binding domain 3), derived from the collapsin response mediator protein 2 (CRMP2)-a cytosolic phosphoprotein, protects neuroblastoma cells against ß-amyloid (Aß) peptide-mediated toxicity through engagement of a phosphorylated CRMP2/NMDAR pathway. Abnormal aggregation of Aß peptides (e.g., Aß25-35) leads to programmed cell death (apoptosis) as well autophagy-both of which contribute to Alzheimer's disease (AD) progression. Here, we asked if ST2-104 affects apoptosis and autophagy in SH-SY5Y neuroblastoma challenged with the toxic Aß25-35 peptide and subsequently mapped the downstream signaling pathways involved. ST2-104 protected SH-SY5Y cells from death following Aß25-35 peptide challenge by reducing apoptosis and autophagy as well as limiting excessive calcium entry. Cytotoxicity of SHY-SY5Y cells challenged with Aß25-35 peptide was blunted by ST2-104. The autophagy activator Rapamycin blunted the anti-apoptotic activity of ST2-104. ST2-104 reversed Aß25-35-induced apoptosis via inhibiting Ca2+/CaM-dependent protein kinase kinase ß (CaMKKß)-mediated autophagy, which was partly enhanced by STO-609 (an inhibitor of CaMKKß). ST2-104 attenuated neuronal apoptosis by inhibiting autophagy through a CaMKKß/AMPK/mTOR signaling hub. These findings identify a mechanism whereby, in the face of Aß25-35, the concerted actions of ST2-104 leads to a reduction in intracellular calcium overload and inhibition of the CaMKKß/AMPK/mTOR pathway resulting in attenuation of autophagy and cellular apoptosis. These findings define a mechanistic framework for how ST2-104 transduces "outside" (calcium channels) to "inside" signaling (CaMKKß/AMPK/mTOR) to confer neuroprotection in AD.

Polystyrene nanoplastics induced learning and memory impairments in mice by damaging the glymphatic system.

The excessive usage of nanoplastics (NPs) has posed a serious threat to the ecological environment and human health, which can enter the brain and then result in neurotoxicity. However, research on the neurotoxic effects of NPs based on different exposure routes and modifications of functional groups is lacking. In this study, the neurotoxicity induced by NPs was studied using polystyrene nanoplastics (PS-NPs) of different modifications (PS, PS-COOH, and PS-NH2). It was found that PS-NH2 through intranasal administration (INA) exposure route exhibited the greatest accumulation in the mice brain after exposure for 7 days. After the mice were exposed to PS-NH2 by INA means for 28 days, the exploratory ability and spatial learning ability were obviously damaged in a dose-dependent manner. Further analysis indicated that these damages induced by PS-NH2 were closely related to the decreased ability of glymphatic system to clear ß-amyloid (Aß) and phosphorylated Tau (P-Tau) proteins, which was ascribed to the loss of aquaporin-4 (AQP4) polarization in the astrocytic endfeet. Moreover, the loss of AQP4 polarization might be regulated by the NF-κB pathway. Our current study establishes the connection between the neurotoxicity induced by PS-NPs and the glymphatic system dysfunction for the first time, which will contribute to future research on the neurotoxicity of NPs.

Monomeric Amyloid Peptide-induced Toxicity in Human Oligodendrocyte Cell Line and Mouse Brain Primary Mixed-glial Cell Cultures: Evidence for a Neuroprotective Effect of Neurosteroid 3α-O-allyl-allopregnanolone.

Amyloid-peptide (Aß) monomeric forms (ABM) occurring in presymptomatic Alzheimer's disease (AD) brain are thought to be devoid of neurotoxicity while the transition/aggregation of ABM into oligomers is determinant for Aß-induced toxicity since Aß is predominantly monomeric up to 3 µM and aggregates over this concentration. However, recent imaging and/or histopathological investigations revealed alterations of myelin in prodromal AD brain in absence of aggregated Aß oligomers, suggesting that ABM may induce toxicity in myelin-producing cells in early AD-stages. To check this hypothesis, here we studied ABM effects on the viability of the Human oligodendrocyte cell line (HOG), a reliable oligodendrocyte model producing myelin proteins. Furthermore, to mimic closely interactions between oligodendrocytes and other glial cells regulating myelination, we investigated also ABM effects on mouse brain primary mixed-glial cell cultures. Various methods were combined to show that ABM concentrations (600 nM-1 µM), extremely lower than 3 µM, significantly decreased HOG cell and mouse brain primary mixed-glial cell survival. Interestingly, flow-cytometry studies using specific cell-type markers demonstrated that oligodendrocytes represent the most vulnerable glial cell population affected by ABM toxicity. Our work also shows that the neurosteroid 3α-O-allyl-allopregnanolone BR351 (250 and 500 nM) efficiently prevented ABM-induced HOG and brain primary glial cell toxicity. Bicuculline (50-100 nM), the GABA-A-receptor antagonist, was unable to block/reduce BR351 effect against ABM-induced HOG and primary glial cell toxicity, suggesting that BR351-evoked neuroprotection of these cells may not depend on GABA-A-receptor allosterically modulated by neurosteroids. Altogether, our results suggest that further exploration of BR351 therapeutic potential may offer interesting perspectives to develop effective neuroprotective strategies.

Melatonin derivative 6a protects Caenorhabditis elegans from formaldehyde neurotoxicity via ADH5.

Formaldehyde (FA) is a carcinogen that is not only widespread in the environment, but is also produced endogenously by metabolic processes. In organisms, FA is converted to formic acid in a glutathione (GSH)-dependent manner by alcohol dehydrogenase 5 (ADH5). The abnormal accumulation of FA in the body can cause a variety of diseases, especially cognitive impairment leading to Alzheimer's disease (AD). In this study, melatonin derivative 6a (MD6a) markedly improved the survival and chemotactic performance of wild-type Caenorhabditis elegans exposed to high concentrations of FA. MD6a lowered FA levels in the nematodes by enhancing the release of covalently-bound GSH from S-hydroxymethyl-GSH in an adh-5-dependent manner. In addition, MD6a protected against mitochondrial dysfunction and cognitive impairment in beta-amyloid protein (Aß) transgenic nematodes by lowering endogenous FA levels and reducing Aß aggregation in an adh-5-dependent manner. Our findings suggest that MD6a detoxifies FA via ADH5 and protects against Aß toxicity by reducing endogenous FA levels in the C. elegans AD models. Thus, ADH5 might be a potential therapeutic target for FA toxicity and AD.

Neuroprotective Effects of Sulforaphane in a rat model of Alzheimer's Disease induced by Aß (1-42) peptides.

The intricate nature of Alzheimer's disease (AD) has presented significant hurdles in the development of effective interventions. Sulforaphane (SFN) is of interest due to its antioxidative, anti-inflammatory, and neuroprotective properties, which could address various aspects of AD pathology. This study explores the potential of SFN in a rat model of AD induced by Aß (1-42) peptides. AD symptoms were triggered in rats by injecting Aß (1-42) peptides directly into their cerebral ventricles. SFN (10 mg/kg and 20 mg/kg), Trigonelline (10 mg/kg), and Pioglitazone (10 mg/kg) were administered in Aß (1-42) treated animals. Behavioral assessments were performed using the Novel Object Recognition tests. Various biochemical parameters, such as soluble Aß (1-42), IRS-S312, GSK-3ß, TNF-α, acetylcholinesterase, nitrite levels, lipid peroxidation, and reduced glutathione activity, were quantified using ELISA kits and spectrophotometric assays. Histopathological analyses included Hematoxylin and Eosin, Crystal Violet, Congo red, and IRS-1 Immunohistochemistry staining. Quantification was performed to assess neuronal loss and Aß plaque burden. The novelty of this study lies in its comprehensive evaluation of SFN's impact on multiple AD-related pathways at dual doses. The Novel Object Recognition test revealed that SFN, especially at higher doses, improved memory deficits induced by Aß (1-42). Biochemically, SFN reduced hippocampal Aß levels, IRS-S312, GSK-3ß, TNF-α, and acetylcholinesterase activity, while increasing glutathione levels, all in a dose-dependent manner. Histopathological analyses further confirmed SFN's protective role against Aß-induced neuronal damage, amyloidosis, and changes in insulin signaling. These results highlight SFN's potential as a multifaceted therapeutic agent for AD, offering a promising avenue for treatment due to its antioxidative, anti-inflammatory, and neuroprotective properties. The inclusion of combination treatments with Trigonelline and Pioglitazone alongside SFN offers insights into potential synergistic effects, which could pave the way for developing combination therapies for AD.

A Cationic Zn-Phthalocyanine Turns Alzheimer's Amyloid ß Aggregates into Non-Toxic Oligomers and Inhibits Neurotoxicity in Culture.

Amyloid ß peptide (Aß) aggregation and deposition are considered the main causes of Alzheimer's disease. In a previous study, we demonstrated that anionic Zn-phthalocyanine (ZnPc) can interact with the Aß peptide and inhibit the fibril-formation process. However, due to the inability of anionic ZnPc to cross the intact blood-brain barrier, we decided to explore the interaction of cationic methylated Zn-phthalocyanine (cZnPc) with the peptide. Using a ThT fluorescence assay, we observed that cZnPc dose-dependently and time-dependently inhibited Aß1-42 fibril levels under in vitro fibril-formation conditions. Electron microscopy revealed that it caused Aß1-42 peptides to form small aggregates. Western blotting and dot immunoblot oligomer experiments demonstrated that cZnPc increased rather than decreased the levels of oligomers from the very early stages of incubation. A binding assay confirmed that cZnPc could bind with the peptide. Docking simulations indicated that the oligomer species of Aß1-42 had a higher ability to interact with cZnPc. ANS fluorescence assay results indicated that cZnPc did not affect the hydrophobicity of the peptide. However, cZnPc significantly increased intrinsic tyrosine fluorescence of the peptide after 8 h of incubation in fibril-formation conditions. Importantly, cell culture experiments demonstrated that cZnPc did not exhibit any toxicity up to a concentration of 10 µM. Instead, it protected a neuronal cell line from Aß1-42-induced toxicity. Thus, our results suggest that cZnPc can affect the aggregation process of Aß1-42, rendering it non-toxic, which could be crucial for the therapy of Alzheimer's disease.

Amyloid beta 1-40 and 1-42 fibril ratios and maturation level cause conformational differences with minimal impact on autophagy and cytotoxicity.

The amyloid ß (Aß) peptide has a central role in Alzheimer's disease (AD) pathology. The peptide length can vary between 37 and 49 amino acids, with Aß1-42 being considered the most disease-related length. However, Aß1-40 is also found in Aß plaques and has shown to form intertwined fibrils with Aß1-42. The peptides have previously also shown to form different fibril conformations, proposed to be related to disease phenotype. To conduct more representative in vitro experiments, it is vital to uncover the impact of different fibril conformations on neurons. Hence, we fibrillized different Aß1-40:42 ratios in concentrations of 100:0, 90:10, 75:25, 50:50, 25:75, 10:90 and 0:100 for either 24 h (early fibrils) or 7 days (aged fibrils). These were then characterized based on fibril width, LCO-staining and antibody-staining. We further challenged differentiated neuronal-like SH-SY5Y human cells with the different fibrils and measured Aß content, cytotoxicity and autophagy function at three different time-points: 3, 24, and 72 h. Our results revealed that both Aß1-40:42 ratio and fibril maturation affect conformation of fibrils. We further show the impact of these conformation changes on the affinity to commonly used Aß antibodies, primarily affecting Aß1-40 rich aggregates. In addition, we demonstrate uptake of the aggregates by neuronally differentiated human cells, where aggregates with higher Aß1-42 ratios generally caused higher cellular levels of Aß. These differences in Aß abundance did not cause changes in cytotoxicity nor in autophagy activation. Our results show the importance to consider conformational differences of Aß fibrils, as this can have fundamental impact on Aß antibody detection. Overall, these insights underline the need for further exploration of the impact of conformationally different fibrils and the need to reliably produce disease relevant Aß aggregates.

Honokiol relieves hippocampal neuronal damage in Alzheimer's disease by activating the SIRT3-mediated mitochondrial autophagy.

BACKGROUND: This work elucidated the effect of honokiol (HKL) on hippocampal neuronal mitochondrial function in Alzheimer's disease (AD). METHODS: APP/PS1 mice were used as AD mice models and exposed to HKL and 3-TYP. Morris water maze experiment was performed to appraise cognitive performance of mice. Hippocampal Aß+ plaque deposition and neuronal survival was evaluated by immunohistochemistry and Nissl staining. Hippocampal neurons were dissociated from C57BL/6 mouse embryos. Hippocampal neuronal AD model was constructed by Aß oligomers induction and treated with HKL, CsA and 3-TYP. Neuronal viability and apoptosis were detected by cell counting kit-8 assay and TUNEL staining. mRFP-eGFP-LC3 assay, MitoSOX Red, dichlorodihydrofluorescein diacetate, and JC-1 staining were performed to monitor neuronal autophagosomes, mitochondrial reactive oxygen species (ROS), neuronal ROS, and mitochondrial membrane potential. Autophagy-related proteins were detected by Western blot. RESULTS: In AD mice, HKL improved cognitive function, relieved hippocampal Aß1-42 plaque deposition, promoted hippocampal neuron survival, and activated hippocampal SIRT3 expression and mitochondrial autophagy. These effects of HKL on AD mice were abolished by 3-TYP treatment. In hippocampal neuronal AD model, HKL increased neuronal activity, attenuated neuronal apoptosis and Aß aggregation, activated SIRT3 and mitochondrial autophagy, reduced mitochondrial and neuronal ROS, and elevated mitochondrial membrane potential. CsA treatment and 3-TYP treatment abrogated the protection of HKL on hippocampal neuronal AD model. The promotion of mitochondrial autophagy by HKL in hippocampal neuronal AD model was counteracted by 3-TYP. CONCLUSIONS: HKL activates SIRT3-mediated mitochondrial autophagy to mitigate hippocampal neuronal damage in AD. HKL may be effective in treating AD.

Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179 Prolong Lifespan and Mitigate Amyloid-ß Toxicity in C. elegans via Distinct Mechanisms.

Background: Recent advances linking gut dysbiosis with neurocognitive disorders such as Alzheimer's disease (AD) suggest that the microbiota-gut-brain axis could be targeted for AD prevention, management, or treatment. Objective: We sought to identify probiotics that can delay Aß-induced paralysis. Methods: Using C. elegans expressing human amyloid-ß (Aß)1-42 in body wall muscles (GMC101), we assessed the effects of several probiotic strains on paralysis. Results: We found that Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179, but not their supernatants or heat-treated forms, delayed paralysis and prolonged lifespan without affecting the levels of amyloid-ß aggregates. To uncover the mechanism involved, we explored the role of two known pathways involved in neurogenerative diseases, namely mitophagy, via deletion of the mitophagy factor PINK-1, and fatty acid desaturation, via deletion of the Δ9 desaturase FAT-5. Pink-1 deletion in GMC101 worms did not modify the life-prolonging and anti-paralysis effects of HA-114 but reduced the protective effect of R0179 against paralysis without affecting its life-prolonging effect. Upon fat5 deletion in GMC101 worms, the monounsaturated C14:1 and C16:1 FAs conserved their beneficial effect while the saturated C14:0 and C16:0 FAs did not. The beneficial effects of R0179 on both lifespan and paralysis remained unaffected by fat-5 deletion, while the beneficial effect of HA-114 on paralysis and lifespan was significantly reduced. Conclusions: Collectively with clinical and preclinical evidence in other models, our results suggest that HA-114 or R0179 could be studied as potential therapeutical adjuncts in neurodegenerative diseases such as AD.

Ganoderic acid a decreased Aß42-induced neurotoxicity in PC12 cells by reduced mitochondrial damage.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Accumulation of ß-amyloid (Aß) in the brain has been recognized as a key factor in the onset and progression of Alzheimer's disease (AD).The accumulation of Aß in the brain catalyzes the production of reactive oxygen species (ROS), which in turn triggers oxidative damage to cellular components such as DNA, lipids, and proteins. In the present study, we investigated the protective effect of Ganoderic acid A (GA.A) against Aß42-induced apoptosis in PC12 cells. Changes in mitochondrial membrane potential indicated that GA.A treats mitochondrial dysfunction by decreasing Aß42 deposition and inhibiting neural protofiber tangle formation. Changes in intracellular Ca2+ and caspase-3 indicated that GA.A reduced mitochondrial damage by Aß42 in PC12 cells, thereby decreasing ROS accumulation and reducing Aß protofiber-induced cytotoxicity. These features suggest that GA.A has great potential as an effective neuroprotective drug in the treatment of Alzheimer's disease.

Formulation and Characterization of Silibinin Entrapped Nano-Liquid Crystals for Activity against Aß1-42 Neurotoxicity in In-Vivo Model.

Silibinin (SIL) Encapsulated Nanoliquid Crystalline (SIL-NLCs) particles were prepared to study neuroprotective effect against amyloid beta (Aß1-42) neurotoxicity in Balb/c mice model. Theses NLCs were prepared through hot emulsification and probe sonication technique. The pharmacodynamics was investigatigated on Aß1-42 intracerebroventricular (ICV) injected Balb/c mice. The particle size, zeta potential and drug loading were optimized to be 153 ± 2.5 nm, -21 mV, and 8.2%, respectively. Small angle X-ray (SAXS) and electron microscopy revealed to crystalline shape of SIL-NLCs. Thioflavin T (ThT) fluroscence and circular dichroism (CD) technique were employed to understand monomer inhibition effect of SIL-NLCs on Aß1-4. In neurobehavioral studies, SIL-NLCs exhibited enhanced mitigation of memory impairment induced on by Aß1-42 in T-maze and new object recognition test (NORT). Whereas biochemical and histopathological estimation of brain samples showed reduction in level of Aß1-42 aggregate, acetylcholine esterase (ACHE) and reactive oxygen species (ROS). SIL-NLCs treated animal group showed higher protection against Aß1-42 toxicity compared to free SIL and Donopezil (DPZ). Therefore SIL-NLCs promises great prospect in neurodegenerative diseases such as Alzheimer's disease.

Polysaccharides from Basella alba Protect Post-Mitotic Neurons against Cell Cycle Re-Entry and Apoptosis Induced by the Amyloid-Beta Peptide by Blocking Sonic Hedgehog Expression.

The amyloid-beta peptide (Aß) is the neurotoxic component in senile plaques of Alzheimer's disease (AD) brains. Previously we have reported that Aß toxicity is mediated by the induction of sonic hedgehog (SHH) to trigger cell cycle re-entry (CCR) and apoptosis in post-mitotic neurons. Basella alba is a vegetable whose polysaccharides carry immunomodulatory and anti-cancer actions, but their protective effects against neurodegeneration have never been reported. Herein, we tested whether polysaccharides derived from Basella alba (PPV-6) may inhibit Aß toxicity and explored its underlying mechanisms. In differentiated rat cortical neurons, Aß25-35 reduced cell viability, damaged neuronal structure, and compromised mitochondrial bioenergetic functions, all of which were recovered by PPV-6. Immunocytochemistry and western blotting revealed that Aß25-35-mediated induction of cell cycle markers including cyclin D1, proliferating cell nuclear antigen (PCNA), and histone H3 phosphorylated at Ser-10 (p-Histone H3) in differentiated neurons was all suppressed by PPV-6, along with mitigation of caspase-3 cleavage. Further studies revealed that PPV-6 inhibited Aß25-35 induction of SHH; indeed, PPV-6 was capable of suppressing neuronal CCR and apoptosis triggered by the exogenous N-terminal fragment of sonic hedgehog (SHH-N). Our findings demonstrated that, in the fully differentiated neurons, PPV-6 exerts protective actions against Aß neurotoxicity via the downregulation of SHH to suppress neuronal CCR and apoptosis.

Histone deacetylase inhibition mitigates cognitive deficits and astrocyte dysfunction induced by amyloid-ß (Aß) oligomers.

BACKGROUND AND PURPOSE: Inhibitors of histone deacetylases (iHDACs) are promising drugs for neurodegenerative diseases. We have evaluated the therapeutic potential of the new iHDAC LASSBio-1911 in Aß oligomer (AßO) toxicity models and astrocytes, key players in neuroinflammation and Alzheimer's disease (AD). EXPERIMENTAL APPROACH: Astrocyte phenotype and synapse density were evaluated by flow cytometry, Western blotting, immunofluorescence and qPCR, in vitro and in mice. Cognitive function was evaluated by behavioural assays using a mouse model of intracerebroventricular infusion of AßO. KEY RESULTS: LASSBio-1911 modulates reactivity and synaptogenic potential of cultured astrocytes and improves synaptic markers in cultured neurons and in mice. It prevents AßO-triggered astrocytic reactivity in mice and enhances the neuroprotective potential of astrocytes. LASSBio-1911 improves behavioural performance and rescues synaptic and memory function in AßO-infused mice. CONCLUSION AND IMPLICATIONS: These results contribute to unveiling the mechanisms underlying astrocyte role in AD and provide the rationale for using astrocytes as targets to new drugs for AD.

The selective butyrylcholinesterase inhibitor UW-MD-95 shows symptomatic and neuroprotective effects in a pharmacological mouse model of Alzheimer's disease.

AIMS: Alzheimer's disease (AD) is a devastating dementia characterized by extracellular amyloid-ß (Aß) protein aggregates and intracellular tau protein deposition. Clinically available drugs mainly target acetylcholinesterase (AChE) and indirectly sustain cholinergic neuronal tonus. Butyrylcholinesterase (BChE) also controls acetylcholine (ACh) turnover and is involved in the formation of Aß aggregates and senile plaques. UW-MD-95 is a novel carbamate-based compound acting as a potent pseudo-irreversible BChE inhibitor, with high selectivity versus AChE, and showing promising protective potentials in AD. METHODS: We characterized the neuroprotective activity of UW-MD-95 in mice treated intracerebroventricularly with oligomerized Aß25-35 peptide using behavioral, biochemical, and immunohistochemical approaches. RESULTS: When injected acutely 30 min before the behavioral tests (spontaneous alternation in the Y-maze, object recognition, or passive avoidance), UW-MD-95 (0.3-3 mg/kg) showed anti-amnesic effects in Aß25-35-treated mice. When injected once a day over 7 days, it prevented Aß25-35-induced memory deficits. This effect was lost in BChE knockout mice. Moreover, the compound prevented Aß25-35-induced oxidative stress (assessed by lipid peroxidation or cytochrome c release), neuroinflammation (IL-6 and TNFα levels or GFAP and IBA1 immunoreactivity) in the hippocampus and cortex, and apoptosis (Bax level). Moreover, UW-MD-95 significantly reduced the increase in soluble Aß1-42 level in the hippocampus induced by Aß25-35. CONCLUSION: UW-MD-95 appeared as a potent neuroprotective compound in the Aß25-35 model of AD, with potentially an impact on Aß1-42 accumulation that could suggest a novel mechanism of neuroprotection.

Cannabidiol protects mouse hippocampal neurons from neurotoxicity induced by amyloid ß-peptide25-35.

Alzheimer's disease (AD), the most prevalent form of dementia worldwide, is a significant health concern, according to the World Health Organization (WHO). The neuropathological diagnostic criteria for AD are based on the deposition of amyloid-ß peptide (Aß) and the formation of intracellular tau protein tangles. These proteins are associated with several overlapping neurodegenerative mechanisms, including oxidative stress, mitochondrial dysfunction, lipid peroxidation, reduced neuronal viability, and cell death. In this context, our study focuses on the potential therapeutic use of cannabidiol (CBD), a non-psychotropic cannabinoid with antioxidant and anti-inflammatory effects. We aim to evaluate CBD's neuroprotective role, particularly in protecting hippocampal neurons from Aß25-35-induced toxicity. Our findings indicate that CBD significantly improves cell viability and decreases levels of lipid peroxidation and oxidative stress. The results demonstrate that CBD possesses a robust potential to rescue cells from induced neurotoxicity through its antioxidant properties. Additionally, the neuroprotective effect of CBD may be associated with the modulation of the endocannabinoid system. These findings suggest that CBD could be a promising compound for adjuvant treatments in neurodegenerative processes triggered by amyloid-ß peptide.

Amyloid-ß oligomer-induced neurotoxicity by exosomal interactions between neuron and microglia.

A hallmark of Alzheimer's disease (AD) is amyloid-ß (Aß) plaque deposition in the brain, causing deficits in cognitive function. Amyloid-beta oligomers (AßOs), the soluble precursor peptides producing Aß plaques, also produce neurotoxicity and microgliosis together with glycolytic reprogramming. Recently, monocarboxylate transporter 1 (MCT1), a key glycolysis regulator, and its ancillary protein, CD147, are found to play an important role in the secretion of exosomes, 30-200 nm vesicles in size, which are considered as toxic molecule carriers in AD. However, the effect of low-concentration AßOs (1 nM) on microglia MCT1 and CD147 expression as well as 1 nM AßOs-treated microglia-derived exosomes on neuronal toxicity remain largely elusive. In this study, 1 nM AßOs induce significant axonopathy and microgliosis. Furthermore, 1 nM AßOs-treated neurons- or microglia-derived exosomes produce axonopathy through their autologous or heterologous uptake by neurons, supporting the role of exosomes as neurotoxicity mediators in AD. Interestingly, MCT1 and CD147 are enhanced in microglia by treatment with 1 nM AßOs or exosomes from 1 nM AßOs-treated- microglia or neurons, suggesting the implication of AßOs-induced enhanced MCT1 and CD147 in microglia with AD neuropathogenesis, which is consistent with the in-silico analysis of the single cell RNA sequencing data from microglia in mouse models of AD and AD patients.