Alzheimer's Disease Therapeutics Research Articles

Neuroprotective Effect of Solid Lipid Nanoparticles Loaded with Lepidium sativum (L.) Seed Bioactive Components Enhance Bioavailability and Wnt/β-Catenin/Camk-II Signaling Cascade in SH-SY5Y Neuroblastoma Cells.

The primary pathological hallmark of Alzheimer's disease (AD) is the formation and accumulation of neurofibrillary tangles and plaques, which result from the aggregation of amyloid-β (Aβ) induced by oxidative stress. The effectiveness of Alzheimer's disease (AD) therapeutics significantly hinges on the drug's bioavailability and its ability to penetrate neuronal cells. The current investigation was designed as a first attempt to examine bio-fabricated Lepidium sativum (LS) seed-extract-loaded solid lipid nanoparticles (SLNps) to increase bioavailability and bioefficacy for the prevention of undifferentiated SH-SY5Y neuronal cells from oxidative stress induced by H2O2 and amyloid-β peptide (Aβ,1-42). The SLNps were fabricated using LS extract as a water phase and hyaluronic acid and chia seed fatty acids as a lipid phase, then confirmed and characterized using UV, Zeta size, and SEM methods. The biological safety of synthesized LS-SLNps has been determined using MTT assay and PI staining (nuclear damage) in hMSCs. LS-SLNp-pretreated neuronal cells were induced with oxidative stress and 2 µM of beta-amyloid (Aβ,1-42) fibrils; furthermore, the neuroprotective potential of LS-SLNps was determined through the quenching of oxidative stress, enhancing mitochondrial oxidative capacity, and immunoregulatory potential. Observations found that cells treated with both H2O2 and beta-amyloid (Aβ,1-42) fibrils showed decreased neuronal cell growth, nuclear damage, and mitochondrial membrane potential due to oxidative stress. However, SH-SY5Y cells pretreated with LS-SLNps for 24 h showed an increase in cell proliferation with uniform morphology and increased mitochondrial membrane potential compared to cells pretreated with LS alone. Gene expression analysis found that LS-SLNps increased the expression of Wnt 3a and 5a, which stimulated the canonical, β-catenin, and non-canonical Camk-II expressions of nerve cell growth factors, confirming the molecular-level reversal of neurodegenerative diseases.

Detection of Femtomolar Amyloid-β Peptides for Early-Stage Identification of Alzheimer's Amyloid-β Aggregation with Functionalized Gold Nanoparticles.

Progressive amyloid-β (Aβ) fibrillar aggregates have long been considered as the pathogenesis of Alzheimer's disease (AD). Biocompatible and stable cysteine-Aβ peptide-conjugated gold nanoparticles (Cys-Aβ@AuNP) are demonstrated as suitable materials for detecting subfemtomolar Aβ peptides in human plasma. Incubation with Aβ peptides causes the Cys-Aβ@AuNP to aggregate and changes its absorption spectra. The spectral change is especially apparent and noticeable when detecting subfemtomolar Aβ peptides, and the aggregates contain only two or three AuNPs. Cys-Aβ@AuNP can also be used to identify early-stage Aβ oligomerization, which is not possible using the conventional method, in which the fluorescence of thioflavin-T is measured. The ability to detect Aβ oligomerization can facilitate therapeutics for AD. In addition, the binding of Aβ peptides by Cys-Aβ@AuNP in combination with centrifugation redirects the conventional Aβ aggregation pathway and can effectively inhibit the formation of toxic Aβ oligomers or fibrils. Therefore, the proposed Cys-Aβ@AuNP can also be used to develop effective therapeutic agents to inhibit Aβ aggregation. The results obtained in this study are expected to open revolutionary ways to both detect and inhibit Aβ aggregation at an early stage.

Novel Pitolisant-Derived Sulfonyl Compounds for Alzheimer Disease.

Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disorder characterized by cognitive decline, memory loss, behavioral changes, and other neurological symptoms. Considering the urgent need for new AD therapeutics, in the present study we designed, synthesized, and evaluated multitarget compounds structurally inspired by sulfonylureas and pitolisant with the aim of obtaining multitarget ligands for AD treatment. Due to the diversity of chemical scaffolds, a novel strategy has been adopted by merging into one structure moieties displaying H3R antagonism and acetylcholinesterase inhibition. Eight compounds, selected by their binding activity on H3R, showed a moderate ability to inhibit acetylcholinesterase activity in vitro, and two of the compounds (derivatives 2 and 7) were also capable of increasing acetylcholine release in vitro. Among the tested compounds, derivative 2 was identified and selected for further in vivo studies. Compound 2 was able to reverse scopolamine-induced cognitive deficits with results comparable to those of galantamine, a drug used in clinics for treating AD. In addition to its efficacy, this compound showed moderate BBB permeation in vitro. Altogether, these results point out that the fragment-like character of compound 2 leads to an optimal starting point for a plausible medicinal chemistry approach for this novel strategy.

Development of multi-targetable chalcone derivatives bearing N-aryl piperazine moiety for the treatment of Alzheimer's disease

The multi-target directed ligand (MTDL) discovery has been gaining immense attention in the development of therapeutics for Alzheimer’s disease (AD). The strategy has been evolved as an auspicious approach suitable to combat the heterogeneity and the multifactorial nature of AD. Therefore, multi-targetable chalcone derivatives bearing N-aryl piperazine moiety were designed, synthesized, and evaluated for the treatment of AD. All the synthesized compounds were screened for thein vitro activityagainst acetylcholinesterase (AChE), butylcholinesterase (BuChE), β-secretase-1 (BACE-1), and inhibition of amyloid β (Aβ) aggregation. Amongst all the tested derivatives, compound 41bearing unsubstituted benzylpiperazine fragment and para-bromo substitution at the chalcone scaffold exhibited balanced inhibitory profile against the selected targets. Compound 41 elicited favourable permeation across the blood–brain barrier in the PAMPA assay. The molecular docking and dynamics simulation studies revealed the binding mode analysis and protein–ligand stability ofthe compound with AChE and BACE-1. Furthermore,itameliorated cognitive dysfunctions and signified memory improvement in thein-vivobehavioural studies (scopolamine-induced amnesia model). Theex vivobiochemical analysis of mice brain homogenates established the reduced AChE and increased ACh levels. The antioxidant activity of compound 41 was accessed with the determination of catalase (CAT) and malondialdehyde (MDA) levels. The findings suggested thatcompound 41, containing a privileged chalcone scaffold, can act as a lead molecule for developing AD therapeutics.

Molecular engineering of a theranostic molecule that detects Aβ plaques, inhibits Iowa and Dutch mutation Aβ self-aggregation and promotes lysosomal biogenesis for Alzheimer's disease.

Extracellular clustering of amyloid-β (Aβ) and an impaired autophagy lysosomal pathway (ALP) are the hallmark features in the early stages of incurable Alzheimer's disease (AD). There is a pressing need to find or develop new small molecules for diagnostics and therapeutics for the early stages of AD. Herein, we report a small molecule, namely F-SLCOOH, which can bind and detect Aβ1-42, Iowa mutation Aβ, Dutch mutation Aβ fibrils and oligomers exhibiting enhanced emission with high affinity. Importantly, F-SLCOOH can readily pass through the blood-brain barrier and shows highly selective binding toward the extracellular Aβ aggregates in real-time in live animal imaging of a 5XFAD mice model. In addition, a high concentration of F-SLCOOH in both brain and plasma of wildtype mice after intraperitoneal administration was found. The ex vivo confocal imaging of hippocampal brain slices indicated excellent colocalization of F-SLCOOH with Aβ positive NU1, 4G8, 6E10 A11 antibodies and THS staining dye, affirming its excellent Aβ specificity and targetability. The molecular docking studies have provided insight into the unique and specific binding of F-SLCOOH with various Aβ species. Importantly, F-SLCOOH exhibits remarkable anti-fibrillation properties against toxic Aβ aggregate formation of Aβ1-42, Iowa mutation Aβ, and Dutch mutation Aβ. F-SLCOOH treatment also exerts high neuroprotective functions and promotes autophagy lysosomal biogenesis in neuronal AD cell models. In summary, the present results suggest that F-SLCOOH is a highly promising theranostic agent for diagnosis and therapeutics of AD.

Unraveling the Role of TREM2 and CD33 in Alzheimer’s Disease

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles. This study investigates the role of two key genes, TREM2 and CD33, in AD pathogenesis. Gene expression profiles from human brain samples and transgenic mouse models were analyzed using data from the Gene Expression Omnibus. Differential gene expression analysis revealed significant upregulation of TREM2 and CD33 in AD samples compared to controls. Analysis of KEGG pathway, a database composed of biological pathway maps, showed TREM2 involvement in osteoclast differentiation and CD33 in hematopoietic cell lineage. String database analysis highlighted both genes' roles in regulating tumor necrosis factor production and cytokine production. Furthermore, TREM2 variants in AD patients were examined, identifying six variants (H157Y, R98W, D87N, T66M, Y38C, and Q33X) exclusive to AD samples. The R47H variant showed the strongest correlation with AD (p<0.001). The following SNPs of CD33 were identified as contributors to AD development: rs3826656, rs3865444, and rs12459419. These findings suggest that TREM2 and CD33 play crucial roles in AD progression, potentially through modulation of microglial function and inflammatory responses. These genes may serve as promising targets for developing novel AD therapeutics and biomarkers.

Executive Summary of 2023 International Conference of the Korean Dementia Association (IC-KDA 2023): A Report From the Academic Committee of the Korean Dementia Association.

The Korean Dementia Association (KDA) has been organizing biennial international academic conferences since 2019, with the International Conference of the KDA (IC-KDA) 2023 held in Busan under the theme 'Beyond Boundaries: Advancing Global Dementia Solutions.' The conference comprised 6 scientific sessions, 3 plenary lectures, and 4 luncheon symposiums, drawing 804 participants from 35 countries. Notably, a Korea-Taiwan Joint Symposium addressed insights into Alzheimer's disease (AD). Plenary lectures by renowned scholars explored topics such as microbiome-related AD pathogenesis, social cognition in neurodegenerative diseases, and genetic frontotemporal dementia (FTD). On the first day, specific presentations covered subjects like the gut-brain axis and neuroinflammation in dementia, blood-based biomarkers in AD, and updates in AD therapeutics. The second day's presentations addressed recent issues in clinical neuropsychology, FTD cohort studies, and the pathogenesis of non-AD dementia. The Academic Committee of the KDA compiles lecture summaries to provide comprehensive understanding of the advanced dementia knowledge presented at IC-KDA 2023.

Tryptophan Metabolism in Alzheimer's Disease with the Involvement of Microglia and Astrocyte Crosstalk and Gut-Brain Axis.

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease characterized by extracellular Amyloid Aβ peptide (Aβ) deposition and intracellular Tau protein aggregation. Glia, especially microglia and astrocytes are core participants during the progression of AD and these cells are the mediators of Aβ clearance and degradation. The microbiota-gut-brain axis (MGBA) is a complex interactive network between the gut and brain involved in neurodegeneration. MGBA affects the function of glia in the central nervous system (CNS), and microbial metabolites regulate the communication between astrocytes and microglia; however, whether such communication is part of AD pathophysiology remains unknown. One of the potential links in bilateral gut-brain communication is tryptophan (Trp) metabolism. The microbiota-originated Trp and its metabolites enter the CNS to control microglial activation, and the activated microglia subsequently affect astrocyte functions. The present review highlights the role of MGBA in AD pathology, especially the roles of Trp per se and its metabolism as a part of the gut microbiota and brain communications. We (i) discuss the roles of Trp derivatives in microglia-astrocyte crosstalk from a bioinformatics perspective, (ii) describe the role of glia polarization in the microglia-astrocyte crosstalk and AD pathology, and (iii) summarize the potential of Trp metabolism as a therapeutic target. Finally, we review the role of Trp in AD from the perspective of the gut-brain axis and microglia, as well as astrocyte crosstalk, to inspire the discovery of novel AD therapeutics.

The application of NLRP3 inflammasome inhibition in Alzheimers disease therapeutics: Clinical benefits, applications, current limitations, and future development

The severe dementia Alzheimers Disease (AD) has been a neurodegenerative disorder that has troubled many for years due to its difficulty in therapeutic development. Negative regulation of the expression and activation of the NLRP3 inflammasome situated in the hippocampus, entorhinal cortex, blood, and other brain-connected tissues have been reported to contribute to the decrease of pathology and effect of AD. This concise review focuses on the various applications, characteristics, efficacy, and potential of inhibitors of the NLRP3 inflammasome at different stages of the NLRP3 activation and expression pathway in addition to their various limitations that would be places of improvement in future pharmaceutical development. NLRP3 inflammasomes such as IC100 and MCC950 are still in a stage of development, with advantages of high specificity and a large range of function, but with a variety of limiting factors such as the lack of clinical trials and deciding studies, therefore causing a therapy with large potential to be still in a position needing great progress.

Inhibition potential against acetylcholinesterase of commercial and extracts of capsaicin and dihydrocapsaicin by in vitro and in silico studies

The present research investigates the amount of capsaicin and dihydrocapsaicin in three parts of chili extracts (pericarp, seeds, and placenta). Moreover, inhibition potential of capsaicin and dihydrocapsaicin, and chili extracts against AChE were also investigated in vitro and in silico study. The results show that placenta extract had more capsaicin (3818.72 mg/kg DW) and dihydrocapsaicin (2788.37 mg/kg DW) than other extracts. The inhibition potential of dihydrocapsaicin against AChE was higher than that of capsaicin and chili extracts. Which corresponded to the Ki value of dihydrocapsaicin (0.85 mM) higher inhibition potential than that of capsaicin (1.20 mM). The stronger interaction of dihydrocapsaicin than capsaicin at the active site of AChE was also supported by the binding affinity value (−7.8 kcal/mol for dihydrocapsaicin and −7.3 kcal/mol for capsaicin). However, the inhibition modes of dihydrocapsaicin and capsaicin were mixed-type inhibition against AChE. Besides, dihydrocapsaicin and capsaicin were surrounded by aromatic amino acids in the active site of AChE, which caused an increase in fluorescence intensity (FI). A similar increase in FI was also observed in the chili extracts (pericarp, seeds, and placenta). Our results show that capsaicinoids (capsaicin and dihydrocapsaicin) from chili extracts are natural inhibitors of AChE and may be applied to therapeutic Alzheimer's disease.

Brain uptake pharmacokinetics of albiglutide, dulaglutide, tirzepatide, and DA5-CH in the search for new treatments of Alzheimer’s and Parkinson’s diseases

ABSTRACT Background A number of peptide incretin receptor agonists (IRAs) show promise as therapeutics for Alzheimer’s disease (AD) and Parkinson’s disease (PD). Transport across the blood–brain barrier (BBB) is one way for IRAs to act directly within the brain. To determine which IRAs are high priority candidates for treating these disorders, we have studied their brain uptake pharmacokinetics. Methods We quantitatively measure the ability of four IRAs to cross the BBB. We injected adult male CD-1 mice intravenously with 125I- or 14C-labeled albiglutide, dulaglutide, DA5-CH, or tirzepatide and used multiple-time regression analyses to measure brain kinetics up to 1 hour. For those IRAs failing to enter the brain 1 h after intravenous injection, we also investigated their ability to enter over a longer time frame (i.e., 6 h). Results Albiglutide and dulaglutide had the fastest brain uptake rates within 1 hour. DA5-CH appears to enter the brain rapidly, reaching equilibrium quickly. Tirzepatide does not appear to cross the BBB within 1 h after iv injection but like albumin, did so slowly over 6 h, presumably via the extracellular pathways. Conclusions We find that IRAs can cross the BBB by two separate processes; one that is fast and one that is slow. Three of the four IRAs investigated here have fast rates of transport and should be taken into consideration for testing as AD and PD therapeutics as they would have the ability to act quickly and directly on the brain as a whole.

Human iPSC‐microglia expressing TREM2 p.R47H risk variant for Alzheimer’s disease do not show a loss‐of‐function phenotype

AbstractBackgroundThe most common TREM2 variant associated with increased risk to develop Alzheimer’s disease (AD) is p.R47H. This variant has been classified as loss‐of‐function, mostly by comparing p.R47H with the common variant in TREM2 over‐expressing cell lines. Whether this holds true when TREM2 is expressed at physiological levels in a disease‐relevant cell type such as human microglia, has not been fully characterized.MethodWe established and thoroughly characterized human iPSC‐derived microglia endogenously expressing TREM2 to assess the effect of p.R47H on TREM2 cellular distribution, TREM2 signaling and microglial functioning. For this study microglia generated from a set of isogenic gene‐edited iPSC lines homozygous for TREM2 knockout (KO) and TREM2 p.R47H were evaluated and compared to microglia from the parental control iPSC line. In addition, microglia generated from iPSC lines obtained from several p.R47H carriers were compared to microglia from iPSC lines obtained from several healthy control non‐carriers. SNP genotyping confirmed the presence of R47H.ResultThe p.R47H and common variant TREM2 were present at similar levels at the cell surface of iPSC‐derived microglia, whereas no expression of TREM2 was detected in the TREM2 KO microglia. Microarray profiling indicated that the microglial transcriptome is very similar between the common variant and p.R47H yet distinct from TREM2 KO microglia. Biochemical evaluation of TREM2 signaling indicated no reduction in TREM2 downstream signaling activation in the p.R47H variant expressing microglia. Similarly, soluble TREM2 levels were increased in culture medium of p.R47H microglia. Finally, analysis of microglial functioning including phagocytosis of artificial and disease‐relevant substrates showed no difference between the p.R47H variant and the common variant, in contrast to TREM2 KO microglia.ConclusionWe conclude that in cultured human iPSC‐derived microglia, the p.R47H variant shows no evidence of a loss‐of‐function mechanism. Future experiments will determine whether this is also the case in microglia in their natural brain environment. Our long‐term goal is to better understand TREM2 biology to support the development of novel therapeutics for AD and other neurodegenerative diseases characterized by TREM2‐mediated neuroinflammation.

Genetic and pharmacologic proteasome augmentation ameliorates Alzheimer’s‐like pathology in animal models of AD

AbstractBackgroundThe proteasome has key roles in neuronal proteostasis, including the removal of misfolded and oxidized proteins, presynaptic protein turnover, and synaptic efficacy and plasticity. Proteasome dysfunction is a prominent feature of Alzheimer’s disease (AD).MethodWe investigate proteasome augmentation through overexpression of a rate limiting proteasome subunit and treatment with proteasome activating peptidomimetics developed by our team in hAPP(J20) mice, MC65 cells overexpressing a C99 fragment of APP and elav‐GS‐GAL4>UAS‐APP;UAS‐BACE1 fly models of AD.ResultWe show that prevention of proteasome dysfunction by genetic manipulation delays mortality, cell death, and cognitive deficits in fly and cell culture AD models. We developed a transgenic mouse with neuronal‐specific proteasome overexpression that, when crossed with an AD mouse model, showed reduced mortality and cognitive deficits. To establish translational relevance, we developed a set of TAT‐based proteasome‐activating peptidomimetics that stably penetrated the blood‐brain barrier and enhanced 20S/26S proteasome activity. These agonists protected against cell death, cognitive decline, and mortality in cell culture, fly, and mouse AD models.ConclusionWe demonstrate proteasome modulation as a viable target for prevention of AD‐like deficits and present a set of novel proteasome agonists as AD therapeutics

Agora: An open‐access platform for the exploration of nascent targets for Alzheimer’s disease therapeutics

AbstractBackgroundAgora (https://agora.adknowledgeportal.org) is an open resource developed to enable Alzheimer’s disease (AD) researchers access to target‐based evidence generated within the translational research portfolio of the National Institute on Aging (NIA). Agora aims to accelerate AD research and maximize therapeutic discovery by sharing information using interactive tools, data visualizations, and summarized evidence.MethodAgora enables the sharing of information about potential AD therapeutic targets by surfacing data visualizations, summary evidence, and results from targeted validation studies. Agora users can browse a list of over 600 targets nominated by the NIA’s Accelerating Medicines Partnership in AD (AMP‐AD) consortium and Target Enablement to Accelerate Therapy Development for AD (TREAT‐AD) centers, and by the broader AD research community; see visualizations and summarized information based on harmonized genome‐wide analyses; use interactive visualizations designed to enable non‐bioinformaticians to evaluate and compare complex multi‐omic data; and access the data underlying these results and visualizations.ResultAgora presents information and results about AD targets using approaches that make this information accessible to a broad spectrum of AD researchers. Recent updates to Agora include 1) presentation of TREAT‐AD target biodomain associations and target ranking scores and 2) a new exploration interface that enables the visual comparison of multi‐omic results across targets.ConclusionThe advancement of promising new AD therapeutics requires efforts that span research groups and specialties across academia and industry. The Agora platform enables the AD research community to unite around target hypotheses to accelerate the investigation of promising new targets and mechanistic hypotheses.

Computational Investigation of the Interaction of Novel Indene Methylene Analogues with Acetylcholinesterase from Both Dynamic and Thermodynamic Perspectives

Background: Torpedo californica acetylcholinesterase (TcAChE) is an important drug development target for Alzheimer's disease (AD) therapeutics. The current in silico study aims to recognise indene methylene-derived compounds acting against TcAChE to gain insight into the molecular interactions. Objective: The current study focused on identifying novel inhibitors for Torpedo californica acetylcholinesterase (TcAChE) by virtual screening, molecular docking, drug-likeness, molecular simulation, and DFT profile for anti-Alzheimer's activity. Methods: Molecular docking, ADMET screening, molecular simulation, and DFT were performed for drug development having anti-Alzheimer's activity related to Torpedo californica acetylcholinesterase (TcAChE). Results: On the AutoDock Vina algorithms, ligands SD-24 [-12.6, -13.1 kcal/mol], SD-30 [-12.5, -12.6 kcal/mol], SD-42 [-11.8, -12.5kcal/mol] showed promising docking and confirmatory redocking scores compared to Donepezil [-8, -10.9 kcal/mol], followed by ADMET screening. The best three complexes were subjected to molecular dynamics simulations (MDSs) over 30 ns to understand the TcAChE dynamics and behavior in a complex with the ligand. MEP and NBO analysis was performed for the DFT/B3LYP theory and 6-311G [d,p] base set and Gaussian 09 package program. For MDSs, the root means square (RMSD) parameter remained stable for 30 ns at 0.25 nm. The ligand-AChE complex formed 2 to 4 satisfactory intermolecular H bonds, which substantiated the stability of the three compounds in the protein binding cluster as potent binders. The LUMO (owest unoccupied molecular orbital)- HOMO (highest occupied molecular orbital) energy gap of the SD24, SD30, and SD42 compounds was 4.0943, 4.2489, and 4.2489 eV, respectively, and stability was ordered as SD24>SD30=SD42. Conclusion: The outcome of in silico studies suggests that SD24, SD30, and SD42 compounds have promising drug-likeness, simulation, and DFT profiles for anti-Alzheimer's activity. However, in vitro and in vivo studies are required to confirm their biological activities.

ISU203 relieves Th17‐mediated neuroinflammation and facilitates removal of amyloid‐β plaques, resulting in the improved cognition in Alzheimer’s disease mouse model

AbstractBackgroundAcid sphingomyelinase (ASM), which localized in endolysosome and plasma membrane, generates ceramide by hydrolyzing sphingomyelin. The enzymatic activity of ASM is elevated in elderly people. Interestingly, it was reported that the activity of ASM was significantly upregulated in patients with several inflammatory diseases, as well as Alzheimer’s disease (AD). Moreover, the inhibition of its activity by treatment of inhibitors or antibody ameliorates the AD pathologies, indicating that ASM is a feasible therapeutic target for AD.MethodTo understand the efficacy and mechanism of action, we administered ISU203 in AD mouse model (APP/PS1) via intraperitoneal injection at 50mg/kg, biw for 8 weeks. To evaluate the cognitive function, Morris Water Maze and Fear conditioning test were utilized. After behavioral tests, mice were sacrificed to demonstrate the deposition of amyloid‐β plaque and phagocytic function of microglia by using immunohistochemistry assay in cortex and hippocampus. To further investigates the neuroinflammation mediated by Th17, pro‐ and anti‐inflammatory gene levels were demonstrated by RT‐qPCR.ResultIn two behavioral tests, we found the improvement of cognitive function of ISU203‐treated group. Morris Water Maze test showed the declined escape latency time by 30%. Furthermore, it showed the significantly increased freezing ratio in ISU203‐treated group in fear conditioning test. ISU203‐treated group also showed alleviation of Th17‐mediated neuroinflammation. In line with this finding, pro‐inflammatory genes were downregulated. On the other hand, anti‐inflammatory genes were upregulated. In addition, we also found the decreased deposition of amyloid‐β plaques, which is an important pathological hallmark of AD. Furthermore, ISU203‐treated group showed that the more microglial cells were colocalized with amyloid‐β plaques, indicating the increased phagocytosis of amyloid‐β by microglia.ConclusionThe treatment of ISU203 showed the relief of Th17‐mediated neuroinflammation and enhanced the removal of amyloid‐β plaques by microglia in AD mouse model. As a result, ISU203 improves cognitive function, suggesting the ISU203 as a novel antibody therapeutics for AD.

Translating AD Clinical Trial Results to Meaningful Benefits: Expectations, Definitions, Challenges and Opportunities.

AbstractBackgroundClinical trials in Alzheimer’s disease (AD) are designed and powered to detect treatment impact on validated research outcome measures necessary for regulatory approval. However, what constitutes a clinically meaningful benefit, how to define, measure and translate it from the results of clinical trial results to multiple stakeholders, including clinicians and patients requires better clarification.MethodsReview and synthesis of recent publications (Assuncao, Sperling, et al. Alz Res Therapy 2022; Petersen, Aisen Andrews, Atri, et al. Alzheimers Dementia. 2023 in press) and AD therapeutics developments to provide overview and frameworks for translating AD clinical trial results to meaningful benefits with respect to expectations, definitions, challenges and opportunities that may resonate with multiple stakeholders, including patients, patient care partners and clinicians.ResultsRational for realistic expectations of putative AD disease‐modifying treatments (DMTs) are reviewed including expectations of not improving symptoms but of slowing disease progression and modestly moderating between‐group (treatment versus placebo) clinical decline. Definitions postulated to represent clinically meaningful benefits are reviewed. Confusion, misunderstanding or misinterpretations in regards to representation of thresholds for meaningful within‐patient progression are discussed, including recent misinterpretation of necessary thresholds for determining meaningful group‐level differences having created misguided expectations for clinical meaningfulness in DMT clinical trial results. Discuss confounding minimal detectable change (MCD) and utilizing between‐group differences (to assess outcome efficacy) with and to define minimal clinically important differences (MCID) (an individual, within‐patient change in outcome assessment). Within‐patient change thresholds are not intended to assess meaningfulness of differences between group‐level changes over time, but may represent meaningful within‐patient trajectories via complementary (e.g. responder/progressor) analyses. Multiple frameworks show the challenges and opportunities to multidimensionally better represent and translate results to face‐valid and patient‐centered representations to resonate with AD stakeholders. These include expanded outcomes (e.g. neuropsychiatric symptoms, socioeconomic burden); patient‐ and caregiver‐reported outcomes; complementary analyses (standardized effect‐sizes, RR/OR, NNT, Time‐to‐Event, Time‐Equivalent‐Gained); and concepts such as predictive benefit (via a disease biomarker/core domain) and cumulative benefits (accrual and potentially increasing over time).ConclusionExpanded data, analyses and frameworks for defining and translating clinically meaningful patient‐centered benefit to multiple stakeholders, particularly patients, care‐partners and clinicians, are proposed.

Novel molecular mechanism driving neuroprotection after soluble epoxide hydrolase inhibition: Insights for Alzheimer's disease therapeutics.

Neuroinflammation is widely recognized as a significant hallmark of Alzheimer's disease (AD). To combat neuroinflammation, the inhibition of the soluble epoxide hydrolase (sEH) enzyme has been demonstrated crucial. Importantly, sEH inhibition could be related to other neuroprotective pathways described in AD. The aim of the study was to unveil new molecular pathways driving neuroprotection through sEH, we used an optimized, potent, and selective sEH inhibitor (sEHi, UB-SCG-51). UB-SCG-51 was tested in neuroblastoma cell line, SH-SY5Y, in primary mouse and human astrocytes cultures challenged with proinflammatory insults and in microglia cultures treated with amyloid oligomers, as well as in mice AD model (5XFAD). UB-SCG-51 (10 and 30 μM) prevented neurotoxic reactive-astrocyte conversion in primary mouse astrocytes challenged with TNF-α, IL-1α, and C1q (T/I/C) combination for 24 h. Moreover, in microglial cultures, sEHi reduced inflammation and glial activity. In addition, UB-SCG-51 rescued 5XFAD cognitive impairment, reducing the number of Amyloid-β plaques and Tau hyperphosphorylation accompanied by a reduction in neuroinflammation and apoptotic markers. Notably, a transcriptional profile analysis revealed a new pathway modulated by sEHi treatment. Specifically, the eIF2α/CHOP pathway, which promoted the endoplasmic reticulum response, was increased in the 5XFAD-treated group. These findings were confirmed in human primary astrocytes by combining sEHi and eIF2α inhibitor (eIF2αi) treatment. Besides, combining both treatments resulted in increased in C3 gene expression after T/I/C compared with the group treated with sEHi alone in cultures. Therefore, sEHi rescued cognitive impairment and neurodegeneration in AD mice model, based on the reduction of inflammation and eIF2α/CHOP signaling pathway. In whole, our results support the concept that targeting neuroinflammation through sEH inhibition is a promising therapeutic strategy to fight against Alzheimer's disease with additive and/or synergistic activities targeting neuroinflammation and cell stress.

Advancing Alzheimer's Therapeutics: Exploring the Impact of Physical Exercise in Animal Models and Patients.

Alzheimer's disease (AD) is the main neurodegenerative disorder characterized by several pathophysiological features, including the misfolding of the tau protein and the amyloid beta (Aβ) peptide, neuroinflammation, oxidative stress, synaptic dysfunction, metabolic alterations, and cognitive impairment. These mechanisms collectively contribute to neurodegeneration, necessitating the exploration of therapeutic approaches with multiple targets. Physical exercise has emerged as a promising non-pharmacological intervention for AD, with demonstrated effects on promoting neurogenesis, activating neurotrophic factors, reducing Aβ aggregates, minimizing the formation of neurofibrillary tangles (NFTs), dampening inflammatory processes, mitigating oxidative stress, and improving the functionality of the neurovascular unit (NVU). Overall, the neuroprotective effects of exercise are not singular, but are multi-targets. Numerous studies have investigated physical exercise's potential in both AD patients and animal models, employing various exercise protocols to elucidate the underlying neurobiological mechanisms and effects. The objective of this review is to analyze the neurological therapeutic effects of these exercise protocols in animal models and compare them with studies conducted in AD patients. By translating findings from different approaches, this review aims to identify opportune, specific, and personalized therapeutic windows, thus advancing research on the use of physical exercise with AD patients.

Emerging Alzheimer's disease therapeutics: promising insights from lipid metabolism and microglia-focused interventions.

More than 55 million people suffer from dementia, with this number projected to double every 20 years. In the United States, 1 in 3 aged individuals dies from Alzheimer's disease (AD) or another type of dementia and AD kills more individuals than breast cancer and prostate cancer combined. AD is a complex and multifactorial disease involving amyloid plaque and neurofibrillary tangle formation, glial cell dysfunction, and lipid droplet accumulation (among other pathologies), ultimately leading to neurodegeneration and neuronal death. Unfortunately, the current FDA-approved therapeutics do not reverse nor halt AD. While recently approved amyloid-targeting antibodies can slow AD progression to improve outcomes for some patients, they are associated with adverse side effects, may have a narrow therapeutic window, and are expensive. In this review, we evaluate current and emerging AD therapeutics in preclinical and clinical development and provide insight into emerging strategies that target brain lipid metabolism and microglial function - an approach that may synergistically target multiple mechanisms that drive AD neuropathogenesis. Overall, we evaluate whether these disease-modifying emerging therapeutics hold promise as interventions that may be able to reverse or halt AD progression.