Aβ Neurotoxicity Research Articles

Helicobacter pylori outer membrane vesicles directly promote Aβ aggregation and enhance Aβ toxicity in APP/PS1 mice

Helicobacter pylori (H. pylori) infection has been found associated with Alzheimer’s disease (AD) with unclear mechanisms. Outer Membrane Vesicles (OMVs) are spherical particles secreted by Gram-negative bacteria. Here we explore the effect of H. pylori OMVs on Aβ aggregation and toxicity. We show intraperitoneally-injected H. pylori OMVs enter the brain and co-localize with Aβ plaques in APP/PS1 mice, accompanied by aggravated Aβ pathology, exacerbated cognitive deficits and synaptic impairment, indicating that H. pylori OMVs promote β-amyloidosis and AD development. The in vitro results further identify that H. pylori OMVs significantly accelerate Aβ aggregation and increase Aβ-induced neurotoxicity. Through lipidomic analysis, we reveal that lipid components, particularly LPC 18:0 in H. pylori OMVs accelerate Aβ aggregation and enhance Aβ neurotoxicity. Moreover, H. pylori OMVs-enhanced Aβ neurotoxicity is mediated by Ca2+. These findings reveal a mechanism of H. pylori OMVs in accelerating AD development in which the bacterial OMVs-originated lipid components play a key role in promoting Aβ aggregation and neurotoxicity.

Targeting Insulin- and Calcium-related Pathways for Potential Treatments for Alzheimer's Disease and Diabetes

: Alzheimer's disease and diabetes are common disorders among the elderly population and have emerged as a major health concern. Both diseases pose considerable risks to one another. Diabetics have a significantly increased probability of getting Alzheimer's disease throughout their lifetime. These diseases are linked because, both share common risk factors such as impaired carbohydrate metabolism, insulin resistance, oxidative stress, inflammatory response, mitochondrial dysfunction, and amyloidosis. Insulin is a vital hormone responsible for bringing extremely high glucose levels back to normal and its receptors available in the hippocampus help in enhancing cognitive function. Insulin resistance consequently serves as a link between both diabetes and AD. Similarly, amylin is another hormone secreted by the pancreas along with insulin. During diabetes, amylin gets oligomerized and forms a neurotoxic complex with Aβ inside the brain, which causes AD to develop. Along with these, another main mechanism influencing AD development is Ca2+ dyshomeostasis. Insulin production from the pancreas is generally aided by Ca2+, but in excess, it can cause dysregulation of many signaling pathways such as CaMKK2, CAMP, CREB, MAPK, STIM\Orai, etc. which can ultimately result in the pathogenesis of AD in diabetic people. In this review, we discussed in detail the pathogenesis of AD associated with diabetes and the mechanisms initiating their progression.

The Dual Role of Amyloid Beta-Peptide in Oxidative Stress and Inflammation: Unveiling Their Connections in Alzheimer's Disease Etiopathology.

Alzheimer's disease (AD) is a progressive neurodegenerative disease, and it is currently the seventh leading cause of death worldwide. It is characterized by the extracellular aggregation of the amyloid β-peptide (Aβ) into oligomers and fibrils that cause synaptotoxicity and neuronal death. Aβ exhibits a dual role in promoting oxidative stress and inflammation. This review aims to unravel the intricate connection between these processes and their contribution to AD progression. The review delves into oxidative stress in AD, focusing on the involvement of metals, mitochondrial dysfunction, and biomolecule oxidation. The distinct yet overlapping concept of nitro-oxidative stress is also discussed, detailing the roles of nitric oxide, mitochondrial perturbations, and their cumulative impact on Aβ production and neurotoxicity. Inflammation is examined through astroglia and microglia function, elucidating their response to Aβ and their contribution to oxidative stress within the AD brain. The blood-brain barrier and oligodendrocytes are also considered in the context of AD pathophysiology. We also review current diagnostic methodologies and emerging therapeutic strategies aimed at mitigating oxidative stress and inflammation, thereby offering potential treatments for halting or slowing AD progression. This comprehensive synthesis underscores the pivotal role of Aβ in bridging oxidative stress and inflammation, advancing our understanding of AD and informing future research and treatment paradigms.

Destabilisation of Alzheimer's amyloid-β protofibrils by Baicalein: mechanistic insights from all-atom molecular dynamics simulations.

Alzheimer's disease (AD) is the most common form of dementia and the fifth leading cause of death globally. Aggregation and deposition of neurotoxic Aβ fibrils in the neural tissues of the brain is a key hallmark in AD pathogenesis. Destabilisation studies of the amyloid-peptide by various natural molecules are highly relevant due to their neuroprotective and therapeutic potential for AD. We performed molecular dynamics (MD) simulation to investigate the destabilisation mechanism of amyloidogenic protofilament intermediate by Baicalein (BCL), a naturally occurring flavonoid. We found that the BCL molecule formed strong hydrophobic contacts with non-polar residues, specifically F19, A21, V24, and I32 of Chain A and B of the pentameric protofibril. Upon binding, it competed with the native hydrophobic contacts of the Aβ protein. BCL loosened the tight packing of the hydrophobic core by disrupting the hydrogen bonds and the prominent D23-K28 inter-chain salt bridges of the protofibril. The decrease in the structural stability of Aβ protofibrils was confirmed by the increased RMSD, radius of gyration, solvent accessible surface area (SASA), and reduced β-sheet content. PCA indicated that the presence of the BCL molecule intensified protofibril motions, particularly affecting residues in Chain A and B regions. Our findings propose that BCL would be a potent destabiliser of Aβ protofilament, and may be considered as a therapeutic agent in treating AD.

Activation of astrocytic NMDA receptors counteracted Aβ-induced reduction of BDNF and elevation of GFAP and complement 3 in the hippocampal astrocytes

N-methyl-D-aspartate receptors (NMDARs) play a crucial role in mediating Amyloid-β (Aβ) synaptotoxicity. Our previous studies have demonstrated an opposite (neuroprotection and neurotoxicity) effect of activating astrocytic and neuronal NMDARs with higher dose (10 μM) of NMDA, an agonist of NMDARs. By contrast, activating neuronal or astrocyitc NMDARs with lower dose (1 μM) of NMDA both exerts neuroprotective effect in Aβ-induced neurotoxicity. However, the underlying mechanism of activating astrocytic NMDARs with lower dose of NMDA to protect against Aβ neurotoxicity remains unclear. Based on our previous related work, in this study, using a co-cultured cell model of primary hippocampal neurons and astrocytes, we further investigated the possible factors involved in 1 μM of NMDA activating astrocytic NMDARs to oppose Aβ-induced synaptotoxicity. Our results showed that activation of astrocytic NMDARs by 1 μM NMDA rescued Aβ-induced reduction of brain-derived neurotrophic factor (BDNF), and inhibited Aβ-induced increase of GFAP, complement 3 (C3) and activation of NF-κB. Furthermore, blockade of astrocytic GluN2A with TCN201 abrogated the ability of 1 μM NMDA to counteract the effects of Aβ decreasing BDNF, and increasing GFAP, C3 and activation of NF-κB. These findings suggest that activation of astrocytic NMDARs protect against Aβ-induced synaptotoxicity probably through elevating BDNF and suppressing GFAP and C3. Our present research provides valuable insights for elucidating the underlying mechanism of astrocytic NMDARs activation resisting the toxic effects of Aβ.

Microglia either promote or restrain TRAIL-mediated excitotoxicity caused by Aβ1−42 oligomers

BackgroundAlzheimer’s disease (AD) features progressive neurodegeneration and microglial activation that results in dementia and cognitive decline. The release of soluble amyloid (Aβ) 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 Aβ plaque pathology in vivo. However, the role of microglia and immune mediators in neurotoxicity induced by soluble Aβ 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.MethodsHippocampal entorhinal brain slice culture (HEBSC) was employed to study mechanisms of Aβ1−42 oligomer-induced neurotoxicity as well as the role of microglia. The roles of glutamate hyperexcitation and immune signaling in Aβ-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 Aβ-treated HEBSCs.ResultsNeurotoxicity induced by soluble Aβ1−42 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 Aβ-induced toxicity. Induction of microglial Gi-signaling with hM4di to prevent pro-inflammatory activation blunted Aβ neurotoxicity, while microglial depletion with CSF1R antagonism worsened neurotoxicity caused by Aβ as well as TRAIL. HEBSCs with repopulated microglia, however, showed a near complete resistance to Aβ-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 Aβ-exposed microglia. mTORC2 and IRF7 were identified as potential targets for intervention.ConclusionMicroglia are key mediators of both protection and neurodegeneration in response to Aβ. Polarizing microglia toward a protective state could be used as a preventative strategy against Aβ-induced neurotoxicity.

Magnetic stirring with iron oxide nanospinners accretes neurotoxic Aβ42 oligomers into phagocytic clearable plaques for Alzheimer's disease treatment

An increasing number of medications have been explored to treat the progressive and irreversible Alzheimer's disease (AD) that stands as the predominant form of dementia among neurodegenerative ailments. However, assertions about toxic side effects of these drugs are a significant hurdle to overcome, calling for drug-free nanotherapeutics. Herein, a new therapeutic strategy devoid of conventional drugs or other cytotoxic species was developed. The constructed superparamagnetic iron oxide nanoparticles (SPIONs) nanospinners can accrete neurotoxic β-amyloid 42 oligomers (oAβ42) into aggregated magnetic plaques (mpAβ) by mechanical rotating force via remote interaction between nanoparticles and the applied magnetic field. While the cellular uptake of mpAβ attained from the magnetic stirring treatment by neuronal cells is severely limited, the facile phagocytic uptake of mpAβ by microglial cells leads to the polarization of the brain macrophages to M2 phenotype and thus the increased anti-inflammatory responses to the treatment. The SPION stirring treatment protects the AD mice from memory deterioration and maintain cognitive ability as evidenced from both nesting and Barnes maze tests. The examination of the oAβ42 injected brain tissues with the stirring treatment showed significant amelioration of functional impairment of neurons, microglia, astrocytes and oligodendrocytes alongside no obvious tissue damage caused by stirring meanwhile complete degradation of SPION was observed at day 7 after the treatment. The in vitro and animal data of this work strongly corroborate that this new modality of undruggable stirring treatment with SPIONs provides a new feasible strategy for developing novel AD treatments.

Structural Reorganization Mechanism of the Aβ42 Fibril Mediated by N-Substituted Oligopyrrolamide ADH-353.

The inhibition of amyloid-β (Aβ) fibrillation and clearance of Aβ aggregates have emerged as a potential pharmacological strategy to alleviate Aβ aggregate-induced neurotoxicity in Alzheimer's disease (AD). Maity et al. shortlisted ADH-353 from a small library of positively charged N-substituted oligopyrrolamides for its notable ability to inhibit Aβ fibrillation, disintegrate intracellular cytotoxic Aβ oligomers, and alleviate Aβ-induced cytotoxicity in the SH-SY5Y and N2a cells. However, the molecular mechanism through which ADH-353 interacts with the Aβ42 fibrils, leading to their disruption and subsequent clearance, remains unclear. Thus, a detailed molecular mechanism underlying the disruption of neurotoxic Aβ42 fibrils (PDB ID 2NAO) by ADH-353 has been illuminated in this work using molecular dynamics simulations. Interestingly, conformational snapshots during simulation depicted the shortening and disappearance of β-strands and the emergence of a helix conformation, indicating a loss of the well-organized β-sheet-rich structure of the disease-relevant Aβ42 fibril on the incorporation of ADH-353. ADH-353 binds strongly to the Aβ42 fibril (ΔGbinding= -142.91 ± 1.61 kcal/mol) with a notable contribution from the electrostatic interactions between positively charged N-propylamine side chains of ADH-353 with the glutamic (Glu3, Glu11, and Glu22) and aspartic (Asp7 and Asp23) acid residues of the Aβ42 fibril. This aligns well with heteronuclear single quantum coherence NMR studies, which depict that the binding of ADH-353 with the Aβ peptide is driven by electrostatic and hydrophobic contacts. Furthermore, a noteworthy decrease in the binding affinity of Aβ42 fibril chains on the incorporation of ADH-353 indicates the weakening of interchain interactions leading to the disruption of the double-horseshoe conformation of the Aβ42 fibril. The illumination of key interactions responsible for the destabilization of the Aβ42 fibril by ADH-353 in this work will greatly aid in designing new chemical scaffolds with enhanced efficacy for the clearance of Aβ aggregates in AD.

Proteomic Analysis Reveals Physiological Activities of Aβ Peptide for Alzheimer's Disease.

With the rapid progress in deciphering the pathogenesis of Alzheimer's disease (AD), it has been widely accepted that the accumulation of misfolded amyloid β (Aβ) in the brain could cause the neurodegeneration in AD. Although much evidence demonstrates the neurotoxicity of Aβ, the role of Aβ in the nervous system are complex. However, more comprehensive studies are needed to understand the physiological effect of Aβ40 monomers in depth. To explore the physiological mechanism of Aβ, we employed mass spectrometry to investigate the altered proteomic events induced by a lower submicromolar concentration of Aβ. Human neuroblastoma SH-SY5Y cells were exposed to five different concentrations of Aβ1-40 monomers and collected at four time points. The proteomic analysis revealed the time-course behavior of proteins involved in biological processes, such as RNA splicing, nuclear transport and protein localization. Further biological studies indicated that Aβ40 monomers may activate PI3K/AKT signaling to regulate p-Tau, Ezrin and MAP2. These three proteins are associated with dendritic morphogenesis, neuronal polarity, synaptogenesis, axon establishment and axon elongation. Moreover, Aβ40 monomers may regulate their physiological forms by inhibiting the expression of BACE1 and APP via activation of the ERK1/2 pathway. A comprehensive exploration of pathological and physiological mechanisms of Aβ is beneficial for exploring novel treatment.

A Biocompatible Hydrogen-Bonded Organic Framework (HOF) as Sonosensitizer and Artificial Enzyme for In-Depth Treatment of Alzheimer's Disease.

Current phototherapeutic approaches for Alzheimer's disease (AD) exhibit restricted clinical outcomes due to the limited physical penetration and comprised brain microenvironment of noninvasive nanomedicine. Herein, a hydrogen-bonded organic framework (HOF) based sonosensitizer is designed and synthesized. Mn-TCPP, a planar molecule where Mn2+ ion is chelated in the core with a large p-conjugated system and 4 carboxylate acid groups, has been successfully used as building blocks to construct an ultrasound-sensitive HOF (USI-MHOF), which can go deep in the brain of AD animal models. The both in vitro and in vivo studies indicate that USI-MHOF can generate singlet oxygen (1O2) and oxidize β-amyloid (Aβ) to inhibit aggregation, consequently attenuating Aβ neurotoxicity. More intriguingly, USI-MHOF exhibits catalase (CAT)- and superoxide dismutase (SOD)-like activities, mitigating neuron oxidative stress and reprograming the brain microenvironment. For better crossing the blood-brain barrier (BBB), the peptide KLVFFAED (KD8) has been covalently grafted to USI-MHOF for improving BBB permeability and Aβ selectivity. Further, in vivo experiments demonstrate a significant reduction of the craniocerebral Aβ plaques and improvement of the cognition deficits in triple-transgenic AD (3×Tg-AD) mice models following deep-penetration ultrasound treatment. The work provides the first example of an ultrasound-responsive biocompatible HOF as non-invasive nanomedicine for in-depth treatment of AD.

Pathological Defects in a Drosophila Model of Alzheimer's Disease and Beneficial Effects of the Natural Product Lisosan G.

Alzheimer's disease (AD) brains are histologically marked by the presence of intracellular and extracellular amyloid deposits, which characterize the onset of the disease pathogenesis. Increasing evidence suggests that certain nutrients exert a direct or indirect effect on amyloid β (Aβ)-peptide production and accumulation and, consequently, on AD pathogenesis. We exploited the fruit fly Drosophila melanogaster model of AD to evaluate in vivo the beneficial properties of Lisosan G, a fermented powder obtained from organic whole grains, on the intracellular Aβ-42 peptide accumulation and related pathological phenotypes of AD. Our data showed that the Lisosan G-enriched diet attenuates the production of neurotoxic Aβ peptides in fly brains and reduces neuronal apoptosis. Notably, Lisosan G exerted anti-oxidant effects, lowering brain levels of reactive oxygen species and enhancing mitochondrial activity. These aspects paralleled the increase in autophagy turnover and the inhibition of nucleolar stress. Our results give support to the use of the Drosophila model not only to investigate the molecular genetic bases of neurodegenerative disease but also to rapidly and reliably test the efficiency of potential therapeutic agents and diet regimens.

Whey protein hydrolysate intervention ameliorates memory deficits in APP/PS1 mice: Unveiling gut microbe–short‐chain fatty acid–brain axis

AbstractThe intricate causes of Alzheimer's disease (AD) hinder effective, lasting treatment. Although the dietary modulation of the brain–gut axis was explored for AD therapy, the exact mechanism remains unclear. This study suggested that 140 days of the whey protein hydrolysate (WPH) intake could attenuate the AD pathologic symptoms in APP/PS1 transgenic mice via a bidirectional action of the gut microbe–SCFA (short‐chain fatty acid)–brain axis. Behavioral tests demonstrated that high‐dose WPH (WPH‐H, 100 mg/kg body weight [bw]) improved passive and recognition memory in mice. Furthermore, WPH‐H significantly reduced amyloid beta 1–42 (Aβ1–42) levels in serum (p < .05) and brain (p < .001) while enhancing serum superoxide dismutase (SOD) activity (p < .01). Brain acetylcholinesterase (p < .01) activity and pro‐inflammatory factors in serum were also reduced. Notably, WPH‐H remodeled gut microbiota composition by increasing Dubosiella and decreasing Bacteroides and norank_f__Ruminococcaceae while stimulating SCFA production. Proteomics indicated that WPH enhanced neurotoxic Aβ autophagy, synaptogenesis, neurotransmitter delivery, and antioxidative stress response via regulated protein expression. Correlation analysis revealed strong links between modified gut microbiota, elevated SCFA levels, and hippocampal protein up‐regulation (Atg4b, Nsfl1c, Tcf20, Nr2f1, and Trappc9) and down‐regulation (Krt1). Overall, the amelioration of memory deficits in APP/PS1 mice through WPH‐H consumption can be attributed to the interconnected interactions among gut microbes, SCFAs, and brain. Our study illuminated the intricate interplay between nutrition, gut health, and memory function, emphasizing WPH's potential in alleviating AD symptoms.

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 (Aβ) is the neurotoxic component in senile plaques of Alzheimer's disease (AD) brains. Previously we have reported that Aβ 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 Aβ toxicity and explored its underlying mechanisms. In differentiated rat cortical neurons, Aβ25-35 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 Aβ25-35-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 Aβ25-35 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 Aβ neurotoxicity via the downregulation of SHH to suppress neuronal CCR and apoptosis.

Formulation and Characterization of Silibinin Entrapped Nano-Liquid Crystals for Activity against Aβ1-42 Neurotoxicity in In-Vivo Model.

Silibinin (SIL) Encapsulated Nanoliquid Crystalline (SIL-NLCs) particles were prepared to study neuroprotective effect against amyloid beta (Aβ1-42) neurotoxicity in Balb/c mice model. Theses NLCs were prepared through hot emulsification and probe sonication technique. The pharmacodynamics was investigatigated on Aβ1-42 intracerebroventricular (ICV) injected Balb/c mice. The particle size, zeta potential and drug loading were optimized to be 153 ± 2.5nm, -21mV, 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) techniquewere employed to understand monomer inhibition effect of SIL-NLCs on Aβ1-4. In neurobehavioral studies, SIL-NLCs exhibited enhanced mitigation of memory impairment induced on by Aβ1-42 in T-maze and new object recognition test (NORT). Whereas biochemical and histopathological estimation of brain samples showed reduction in level of Aβ1-42 aggregate, acetylcholine esterase (ACHE) and reactive oxygen species (ROS). SIL-NLCs treated animal group showed higher protection against Aβ1-42 toxicity compared to free SIL and Donopezil (DPZ). Therefore SIL-NLCs promises great prospect in neurodegenerative diseases such as Alzheimer's disease.

Cryo-EM structures reveal tau filaments from Down syndrome adopt Alzheimer’s disease fold

Down syndrome (DS) is a common genetic condition caused by trisomy of chromosome 21. Among their complex clinical features, including musculoskeletal, neurological, and cardiovascular disabilities, individuals with DS have an increased risk of developing progressive dementia and early-onset Alzheimer’s disease (AD). This dementia is attributed to the increased gene dosage of the amyloid-β (Aβ) precursor protein gene, the formation of self-propagating Aβ and tau prion conformers, and the deposition of neurotoxic Aβ plaques and tau neurofibrillary tangles. Tau amyloid fibrils have previously been established to adopt many distinct conformations across different neurodegenerative conditions. Here, we report the characterization of brain samples from four DS cases spanning 36–63 years of age by spectral confocal imaging with conformation-specific dyes and cryo–electron microscopy (cryo-EM) to determine structures of isolated tau fibrils. High-resolution structures revealed paired helical filament (PHF) and straight filament (SF) conformations of tau that were identical to those determined from AD cases. The PHFs and SFs are made of two C-shaped protofilaments, each containing a cross-β/β-helix motif. Similar to filaments from AD cases, most filaments from the DS cases adopted the PHF form, while a minority (approximately 20%) formed SFs. Samples from the youngest individual with no documented dementia had sparse tau deposits. To isolate tau for cryo-EM from this challenging sample we used a novel affinity-grid method involving a graphene oxide surface derivatized with anti-tau antibodies. This method improved isolation and revealed that primarily tau PHFs and a minor population of chronic traumatic encephalopathy type II–like filaments were present in this youngest case. These findings expand the similarities between AD and DS to the molecular level, providing insight into their related pathologies and the potential for targeting common tau filament folds by small-molecule therapeutics and diagnostics.

Amygdala neuronal dyshomeostasis via 5-HT receptors mediates mood and cognitive defects in Alzheimer's disease.

Behavioral changes or neuropsychiatric symptoms (NPSs) are common features in dementia and are associated with accelerated cognitive impairment and earlier deaths. However, how NPSs are intertwined with cognitive decline remains elusive. In this study, we identify that the basolateral amygdala (BLA) is a key brain region that is associated with mood disorders and memory decline in the AD course. During the process from pre- to post-onset in AD, the dysfunction of parvalbumin (PV) interneurons and pyramidal neurons in the amygdala leads to hyperactivity of pyramidal neurons in the basal state and insensitivity to external stimuli. We further demonstrate that serotonin (5-HT) receptors in distinct neurons synergistically regulate the BLA microcircuit of AD rather than 5-HT levels, in which both restrained inhibitory inputs by excessive 5-HT1AR signaling in PV interneurons and depolarized pyramidal neurons via upregulated 5-HT2AR contribute to aberrant neuronal hyperactivity. Downregulation of these two 5-HT receptors simultaneously enables neurons to resist β-amyloid peptides (Aβ) neurotoxicity and ameliorates the mood and cognitive defects. Therefore, our study reveals a crucial role of 5-HT receptors for regulating neuronal homeostasis in AD pathogenesis, and this would provide early intervention and potential targets for AD cognitive decline.

Mechanism of action and clinical trial results of Lecanemab (Leqembi® 200 ‍mg, 500 ‍mg for Intravenous Infusion), a novel treatment for Alzheimer's disease

Lecanemab is a humanized monoclonal antibody directed against human soluble amyloid-β aggregates. It was developed for the treatment of early Alzheimer's disease (mild cognitive impairment or mild dementia stage of Alzheimer's disease). Among the amyloid-β (Aβ) involved in Alzheimer's disease, Lecanemab selectively binds to the highly neurotoxic Aβ protofibrils, and is thought to reduce Aβ protofibrils and amyloid plaques (Aβ plaques) in the brain. The efficacy and safety of Lecanemab in early Alzheimer's disease were investigated in an international Phase II placebo-controlled study (Study 201) and an international Phase III placebo-controlled study (Study 301). Both studies included Japanese subjects. Lecanemab was given accelerated approval in the United States in January 2023, followed by traditional approval in July 2023. In Japan, it was approved for "control of the progression of mild cognitive impairment or mild dementia stage of Alzheimer's disease" in September 2023, and was added to the NHI drug price list in December 2023.

Quercetin-3-O-glc-1-3-rham-1-6-glucoside decreases Aβ production, inhibits Aβ aggregation and neurotoxicity, and prohibits the production of inflammatory cytokines

Alzheimer's disease (AD) is a progressive neurodegenerative disease with the hallmark of aggregation of beta-amyloid (Aβ) into extracellular fibrillar deposition. Accumulating evidence suggests that soluble toxic Aβ oligomers exert diverse roles in neuronal cell death, oxidative stress, neuroinflammation, and the eventual pathogenesis of AD. Aβ is derived from the sequential cleavage of amyloid-β precursor protein (APP) by β-secretase (BACE1) and γ-secretase. The current effect of single targeting is not ideal for the treatment of AD. Therefore, developing multipotent agents with multiple properties, including anti-Aβ generation and anti-Aβ aggregation, is attracting more attention for AD treatment. Previous studies indicated that Quercetin was able to attenuate the effects of several pathogenetic factors in AD. Here, we showed that naturally synthesized Quercetin-3-O-glc-1-3-rham-1-6-glucoside (YCC31) could inhibit Aβ production by reducing β-secretase activity. Further investigations indicated that YCC31 could suppress toxic Aβ oligomer formation by directly binding to Aβ. Moreover, YCC31 could attenuate Aβ-mediated neuronal death, ROS and NO production, and pro-inflammatory cytokines release. Taken together, YCC31 targeting multiple pathogenetic factors deserves further investigation for drug development of AD.

Post-translational modifications of beta-amyloid alter its transport in the blood-brain barrier in vitro model.

One of the hallmarks of Alzheimer's disease (AD) is the accumulation of beta-amyloid peptide (Aβ) leading to formation of soluble neurotoxic Aβ oligomers and insoluble amyloid plaques in various parts of the brain. Aβ undergoes post-translational modifications that alter its pathogenic properties. Aβ is produced not only in brain, but also in the peripheral tissues. Such Aβ, including its post-translationally modified forms, can enter the brain from circulation by binding to RAGE and contribute to the pathology of AD. However, the transport of modified forms of Aβ across the blood-brain barrier (BBB) has not been investigated. Here, we used a transwell BBB model as a controlled environment for permeability studies. We found that Aβ42 containing isomerized Asp7 residue (iso-Aβ42) and Aβ42 containing phosphorylated Ser8 residue (pS8-Aβ42) crossed the BBB better than unmodified Aβ42, which correlated with different contribution of endocytosis mechanisms to the transport of these isoforms. Using microscale thermophoresis, we observed that RAGE binds to iso-Aβ42 an order of magnitude weaker than to Aβ42. Thus, post-translational modifications of Aβ increase the rate of its transport across the BBB and modify the mechanisms of the transport, which may be important for AD pathology and treatment.

Brazilin-7-2-butenoate inhibits amyloid β-protein aggregation, alleviates cytotoxicity, and protects Caenorhabditis elegans

The fibrillogenesis of amyloid β-protein (Aβ) gradually accumulates to form neurotoxic Aβ aggregates in the human brain, which is the direct cause of Alzheimer's disease (AD) related symptoms. There are currently no effective therapies for AD. Brazilin, a natural polyphenol, inhibits Aβ fibrillogenesis, disrupts the mature fibrils and alleviates the corresponding cytotoxicity, but it also has the high toxic. Therefore, brazilin-7-2-butenoate (B-7-2-B), a brazilin derivative, was designed and synthesized. B-7-2-B exhibited lower toxicity and stronger inhibitory effect on Aβ aggregation than brazilin. B-7-2-B could prevent the formation of Aβ fibrils and oligomers, and depolymerize pre-formed aggregates in a dose-dependent manner. Furthermore, B-7-2-B prominently alleviated the cytotoxicity and the oxidative stress induced by Aβ aggregates in PC12 cells. The protective impacts of B-7-2-B were further demonstrated by using the Caenorhabditis elegans model, including decreasing the extent of Aβ aggregation, improving the motility and sensation disorders. Eventually, B-7-2-B was proven to be no apparent damage to worms. In summarize, it can be concluded that B-7-2-B has the potential as a drug for treating AD.