Multifaceted neuroprotective approach of Trolox in Alzheimer's disease mouse model: targeting Aß pathology, neuroinflammation, oxidative stress, and synaptic dysfunction.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by the deposition of amyloid beta (Aß) plaques and neurofibrillary tangles (NFTs) in the brain. The accumulation of these aggregated proteins causes memory and synaptic dysfunction, neuroinflammation, and oxidative stress. This research study is significant as it aims to assess the neuroprotective properties of vitamin E (VE) analog Trolox in an Aß1 - 42-induced AD mouse model. Aß1 - 42 5µL/5min/mouse was injected intracerebroventricularly (i.c.v.) into wild-type adult mice brain to induce AD-like neurotoxicity. For biochemical analysis, Western blotting and confocal microscopy were performed. Remarkably, intraperitoneal (i.p.) treatment of Trolox (30 mg/kg/mouse for 2 weeks) reduced the AD pathology by reducing the expression of Aß, phosphorylated tau (p-tau), and ß-site amyloid precursor protein cleaving enzyme1 (BACE1) in both cortex and hippocampus regions of mice brain. Furthermore, Trolox-treatment decreased neuroinflammation by inhibiting Toll-like receptor 4 (TLR4), phosphorylated nuclear factor-κB (pNF-κB) and interleukin-1ß (IL-1ß), and other inflammatory biomarkers of glial cells [ionized calcium-binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP)]. Moreover, Trolox reduced oxidative stress by enhancing the expression of nuclear factor erythroid-related factor 2 (NRF2) and heme oxygenase 1 (HO1). Similarly, Trolox-induced synaptic markers, including synaptosomal associated protein 23 (SNAP23), synaptophysin (SYN), and post-synaptic density protein 95 (PSD-95), and memory functions in AD mice. Our findings could provide a useful and novel strategy for investigating new medications to treat AD-associated neurodegenerative diseases.

Expressing miR-282 mitigates Aß42-induced neurodegeneration in Alzheimer's model in Drosophila.

Alzheimer's disease is a complex neurodegenerative condition characterized by the accumulation of amyloid beta plaques, leading to memory loss, cognitive decline, and impaired autonomous behavior. Despite extensive research, an effective treatment remains elusive. The buildup of amyloid beta plaques (Aß42) in the brain causes oxidative stress and disrupts normal molecular signaling, adversely affecting neuron function. Previous research has identified factors that can either exacerbate or mitigate neurodegenerative diseases. Our study aimed to uncover new factors involved in the pathogenesis of Alzheimer's disease. Using Drosophila as a model organism, we employed the Gal4/UAS system to express human Aß42 in the flies' retinal neurons which led to neurodegenerative changes in their compound eyes. To identify genetic modifiers, we conducted a screen by co-expressing microRNAs and found that miR-282 acts as a suppressor. Overexpressing miR-282 in the GMR > Aß42 background reduced Aß42-induced neurodegeneration. Further analysis using prediction tools and RNA interference experiments identified three potential downstream targets of miR-282: calpain-B, knot, and scabrous. Downregulating these genes via RNA interference in the GMR > Aß42 background mitigated neurodegeneration. Our research highlights miR-282 as a novel molecule that may influence the progression of Alzheimer's disease, offering potential avenues for future therapeutic or diagnostic developments.

Real-time analysis of the biomolecular interaction between gelsolin and Aß1-42 monomer and its implication for Alzheimer's disease.

Biomolecular interaction acts a pivotal part in understanding the mechanisms underlying the development of Alzheimer's disease (AD). Herein, we built a biosensing platform to explore the interaction between gelsolin (GSN) and different ß-amyloid protein 1-42 (Aß1-42) species, including Aß1-42 monomer (m-Aß), Aß1-42 oligomers with both low and high levels of aggregation (LLo-Aß and HLo-Aß) via dual polarization interferometry (DPI). Real-time molecular interaction process and kinetic analysis showed that m-Aß had the strongest affinity and specificity with GSN compared with LLo-Aß and HLo-Aß. The impact of GSN on inhibiting aggregation of Aß1-42 and solubilizing Aß1-42 aggregates was evaluated by circular dichroism (CD) spectroscopy. The maintenance of random coil structure of m-Aß and the reversal of ß-sheet structure in HLo-Aß were observed, demonstrating the beneficial effects of GSN on preventing Aß from aggregation. In addition, the structure of m-Aß/GSN complex was analyzed in detail by molecular dynamics (MD) simulation and molecular docking. The specific binding sites and crucial intermolecular forces were identified, which are believed to stabilize m-Aß in its soluble state and to inhibit the fibrilization of Aß1-42. Combined theoretical simulations and experiment results, we speculate that the success of GSN sequestration mechanism and the balance of GSN levels in cerebrospinal fluid and plasma of AD subjects may contribute to a delay in AD progression. This research not only unveils the molecular basis of the interaction between GSN and Aß1-42, but also provides clues to understanding the crucial functions of GSN in AD and drives the development of AD drugs and therapeutic approaches.

Japanese Subgroup Analyses from EMERGE and ENGAGE, Phase 3 Clinical Trials of Aducanumab in Patients with Early Alzheimer's Disease.

BACKGROUND: Global prevalence and incidence of dementia continue to rise at a rapid rate. There is a need for new Alzheimer's disease (AD) treatments globally. Aducanumab is a human monoclonal antibody that selectively targets aggregated soluble amyloid beta oligomers and insoluble amyloid beta fibrils. In June 2021, aducanumab was approved by the US Food and Drug Administration for the treatment of AD under the accelerated approval pathway. OBJECTIVES: We evaluated the efficacy, safety, biomarker and pharmacokinetics (PK) of aducanumab in Japanese subgroups in EMERGE and ENGAGE studies. DESIGN: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early AD (mild cognitive impairment due to AD or mild AD dementia). SETTING: These studies involved 348 sites in 20 countries. PARTICIPANTS: Participants enrolled in Japan included 121 (7.4% of total 1638 in EMERGE) and 100 (6.1% of total 1647 in ENGAGE) patients (aged 50-85 years with confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to AD or mild AD dementia. INTERVENTION: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (6 or 10 mg/kg target dose) or placebo via IV infusion once every 4 weeks over 76 weeks. MEASUREMENTS: The primary outcome measure was change from baseline to Week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; biomarker endpoints (amyloid PET and plasma p-tau181); serum PK profiles and immunogenicity. RESULTS: Results from the Japanese subgroup analyses were generally consistent with those of the overall study population across endpoints, while a lower mean body weight (kg) and a smaller proportion of ApoE ε4 carriers were observed in the Japanese subgroup population. A treatment effect was observed in favor of aducanumab on the primary and secondary efficacy endpoints at Week 78 in EMERGE, but not ENGAGE. The incidence and type of adverse events in the Japanese subgroups were generally comparable to those observed in the overall study population; amyloid related imaging abnormalities (ARIA) were common treatment-related adverse events that appeared to be related to the aducanumab dose. ARIA incidence was generally lower in the Japanese subgroup compared with the overall population. Consistent with the overall data set, a robust dose-dependent decrease in amyloid beta levels as assessed with amyloid-PET and plasma p-tau181 was observed. Serum PK profiles and immunogenicity of aducanumab in Japanese population were consistent with the non-Japanese population. CONCLUSION: Efficacy, safety, biomarker, and PK profiles of aducanumab were consistent between the Japanese subgroup and the overall population. A positive treatment effect of aducanumab on efficacy endpoints was observed in EMERGE, but not in ENGAGE.

Can Targeted Protein Degradation Technology Provide a Potential Breakthrough in the Development of Anti-AD Drugs?

Recent advancements in Alzheimer's disease (AD) research have led to the approval of lecanemab and donanemab, highlighting the effectiveness of amyloid-beta (Aß) degradation as a treatment for AD. The prospect of small molecule Aß degraders as a potential treatment, which utilizes emerging targeted protein degradation technology, is exciting, given their ability to address some of the limitations of current therapies and their promising future in AD treatment. Despite facing challenges, these degraders are poised to become a future treatment option, harnessing scientific breakthroughs for more targeted and effective AD therapy.

Association Between Type 2 Diabetes Mellitus and Alzheimer's Disease: Common Molecular Mechanism and Therapeutic Targets.

Diabetes mellitus (DM) and Alzheimer's disease (AD) rates are rising, mirroring the global trend of an aging population. Numerous epidemiological studies have shown that those with Type 2 diabetes (T2DM) have an increased risk of developing dementia. These degenerative and progressive diseases share some risk factors. To a large extent, the amyloid cascade is responsible for AD development. Neurofibrillary tangles induce neurodegeneration and brain atrophy; this chain reaction begins with hyperphosphorylation of tau proteins caused by progressive amyloid beta (Aß) accumulation. In addition to these processes, it seems that alterations in brain glucose metabolism and insulin signalling lead to cell death and reduced synaptic plasticity in AD, before the onset of symptoms, which may be years away. Due to the substantial evidence linking insulin resistance in the brain with AD, researchers have coined the name "Type 3 diabetes" to characterize the condition. We still know little about the processes involved, even though current animal models have helped illuminate the links between T2DM and AD. This brief overview discusses insulin and IGF-1 signalling disorders and the primary molecular pathways that may connect them. The presence of GSK-3ß in AD is intriguing. These proteins' association with T2DM and pancreatic ß-cell failure suggests they might be therapeutic targets for both disorders.

Associations between misfolded alpha-synuclein aggregates and Alzheimer's disease pathology in vivo.

INTRODUCTION: We examined the relations of misfolded alpha synuclein (α-synuclein) with Alzheimer's disease (AD) biomarkers in two large independent cohorts. METHODS: We included Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably Two (BioFINDER-2) and Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n = 2315, cognitively unimpaired, mild cognitive impairment, AD dementia) who had cross-sectional cerebrospinal fluid (CSF) α-synuclein measurement from seed-amplification assay as well as cross-sectional and longitudinal amyloid beta (Aß) and tau levels (measured in CSF and/or by positron emission tomography). All analyses were adjusted for age, sex, and cognitive status. RESULTS: Across cohorts, the main biomarker associated with α-synuclein positivity at baseline was higher levels of Aß pathology (all p values ≤ 0.02), but not tau. Looking at longitudinal measures of AD biomarkers, α-synuclein -positive participants had a statistically significant faster increase of Aß load, although of modest magnitude (1.11 Centiloid/year, p = 0.02), compared to α-synuclein -negative participants in BioFINDER-2 but not in ADNI. DISCUSSION: We showed associations between concurrent misfolded α-synuclein and Aß levels, providing in vivo evidence of links between these two molecular disease pathways in humans. HIGHLIGHTS: Amyloid beta (Aß), but not tau, was associated with alpha-synuclein (α-synuclein) positivity. Such association was consistent across two cohorts, beyond the effect of age, sex, and cognitive status. α-synuclein-positive participants had a small, statistically significant faster increase in Aß positron emission tomography levels in one of the two cohorts.

Minocycline mitigates Aß and TAU pathology, neuronal dysfunction, and death in the PSEN1 E280A cholinergic-like neurons model of familial Alzheimer's disease.

Familial Alzheimer's disease (FAD) presenilin 1 E280A (PSEN1 E280A) is a severe neurological condition due to the loss of cholinergic neurons (ChNs), accumulation of amyloid beta (Aß), and abnormal phosphorylation of the TAU protein. Up to date, there are no effective therapies available. The need for innovative treatments for this illness is critical. We found that minocycline (MC, 5 µM) was innocuous toward wild-type (WT) PSEN1 ChLNs but significantly (i) reduces the accumulation of intracellular Aß by -69%, (ii) blocks both abnormal phosphorylation of the protein TAU at residue Ser202/Thr205 by -33% and (iii) phosphorylation of the proapoptotic transcription factor c-JUN at residue Ser63/Ser73 by -25%, (iv) diminishes oxidized DJ-1 at Cys106-SO3 by -29%, (v) downregulates the expression of transcription factor TP53, (vi) BH-3-only protein PUMA, and (vii) cleaved caspase 3 (CC3) by -33, -86, and -78%, respectively, compared with untreated PSEN1 E280A ChLNs. Additionally, MC increases the response to ACh-induced Ca2+ influx by +92% in mutant ChLNs. Oxygen radical absorbance capacity (ORAC) and ferric ion-reducing antioxidant power (FRAP) analysis showed that MC might operate more efficiently as a hydrogen atom transfer agent than a single electron transfer agent. In silico molecular docking analysis predicts that MC binds with high affinity to Aß (Vina Score -6.6 kcal/mol), TAU (VS -6.5 kcal/mol), and caspase 3 (VS -7.1 kcal/mol). Taken together, our findings suggest that MC demonstrates antioxidant, anti-amyloid, and anti-apoptosis activity and promotes physiological ACh-induced Ca2+ influx in PSEN1 E280A ChLNs. The MC has therapeutic potential for treating early-onset FAD.

Self- and study partner-reported cognitive decline in older adults without dementia: The role of α-synuclein and amyloid biomarkers in the Alzheimer's Disease Neuroimaging Initiative.

INTRODUCTION: Subjective cognitive decline (SCD) may be an early marker of Alzheimer's disease (AD) pathology. Until recently, it was impossible to measure biomarkers specific for α-synuclein pathology; therefore, its association with subjective reports of cognitive decline is unknown. METHODS: Alzheimer's Disease Neuroimaging Initiative participants without dementia (n = 918) were classified as positive or negative for amyloid beta (Aß+ or Aß-) and α-synuclein (α-syn+ or α-syn-) biomarkers. Self- and study partner-reported cognitive decline was measured with the Everyday Cognition (ECog) questionnaire. RESULTS: Per self-report, Aß+/α-syn+ had the greatest cognitive decline. Aß-/α-syn+ did not differ from Aß-/α-syn- across ECog scores. Study partner-reported results had a similar pattern, but Aß+/α-syn- and Aß+/α-syn+ did not differ across ECog scores. Mild cognitive impairment classification moderated the study partner-reported memory score. DISCUSSION: While α-syn+ alone did not increase subjective reports of cognitive decline, Aß+/α-syn+ had the most self- and study partner-rated cognitive decline. Therefore, the presence of multiple pathologies was associated with greater SCD. HIGHLIGHTS: Cerebrospinal fluid α-synuclein (α-syn) seed amplification assay was used to determine α-syn positivity. Amyloid beta (Aß)-/α-syn-, Aß-/α-syn+, Aß+/α-syn-, and Aß+/α-syn+ biomarker groups were created. Aß+/α-syn+ had greater subjective cognitive decline (SCD) than the other biomarker groups. Aß-/α-syn+ did not differ from Aß-/α-syn- across self- or study-partner reported SCD scores. Study partner-reported subjective memory results were largely driven by participants with mild cognitive impairment.

Activation of astrocytic NMDA receptors counteracted Aß-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-ß (Aß) 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 Aß-induced neurotoxicity. However, the underlying mechanism of activating astrocytic NMDARs with lower dose of NMDA to protect against Aß 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 Aß-induced synaptotoxicity. Our results showed that activation of astrocytic NMDARs by 1 µM NMDA rescued Aß-induced reduction of brain-derived neurotrophic factor (BDNF), and inhibited Aß-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 Aß decreasing BDNF, and increasing GFAP, C3 and activation of NF-κB. These findings suggest that activation of astrocytic NMDARs protect against Aß-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 Aß.

Medial temporal lobe atrophy patterns in early-versus late-onset amnestic Alzheimer's disease.

BACKGROUND: The medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimer's disease (EOAD). Yet, detailed examination of MTL subfields and drivers of atrophy in amnestic EOAD is lacking. METHODS: BioFINDER-2 participants with memory impairment, abnormal amyloid-ß and tau-PET were included. Forty-one amnestic EOAD individuals ≤65 years and, as comparison, late-onset AD (aLOAD, ≥70 years, n = 154) and amyloid-ß-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured. RESULTS: AD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups: aLOAD showed thinner entorhinal cortices than aEOAD; aEOAD showed thinner parietal regions than aLOAD. aEOAD showed lower white matter hyperintensities than aLOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity were found. CONCLUSIONS: We found evidence for MTL atrophy in amnestic EOAD and overall similar levels to aLOAD of MTL tau pathology and co-pathologies.

Aß remotely and locally facilitates Alzheimer's disease tau spreading.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta plaques initiated approximately 2 decades before the symptom onset followed by build-up and spreading of neurofibrillary tau aggregates. Although it has been suggested that the amyloid-beta amplifies tau spreading the observed spatial disparity called it into question. Yet, it is unclear how neocortical amyloid-beta remotely affects early pathological tau, triggering it to leave the early formation area, and how amyloid-beta facilitates tau aggregate spreading throughout cortical regions. I aimed to investigate how amyloid-beta can facilitate tau spreading through neuronal connections in the Alzheimer's disease pathological process by combining functional magnetic resonance imaging normative connectomes and longitudinal in vivo molecular imaging data. In total, the imaging data of 317 participants, including 173 amyloid-beta-negative non-demented and 144 amyloid-beta -positive non-demented participants, have entered the study from Alzheimer's Disease Neuroimaging Initiative. Furthermore, normative resting-state functional magnetic resonance imaging connectomes were used to model tau spreading through functional connections. It was observed that the amyloid-beta in regions with the highest deposition (amyloid-beta epicenter) is remotely associated with connectivity-based spreading of tau pathology. Moreover, amyloid-beta in regions that exhibit the highest tau pathology (tau epicenter) is associated with increased connectivity-based tau spreading to non-epicenter regions. The findings provide a further explanation for a long-standing question of how amyloid-beta can affect tau aggregate spreading through neuronal connections despite spatial incongruity. The results suggest that amyloid-beta pathology can remotely and locally facilitate connectivity-based spreading of tau aggregates.

Emoxypine succinate modulates behavioral and molecular responses in zebrafish model of iron Overload-Induced neuroinflammation via CDK5/GSK3- ß and NLRP3 inflammasome pathway.

Excessive iron accumulation in the brain plays a significant role in neurodegenerative processes, contributing to the pathogenesis of Alzheimer's disease (AD). AD, a prominent neurological disorder affecting the central nervous system, is characterized by the accumulation of beta-amyloid (Aß) and tau phosphorylation. This accumulation leads to the subsequent development of cognitive impairments, particularly in learning and memory functions. This study investigates the neuroprotective effects of emoxypine succinate in a zebrafish model of iron overload-induced neurodegeneration. Iron was administered to the zebrafish for 28 days to induce neurodegeneration. Following induction, Emoxypine succinate was employed as a treatment intervention for 14 days (concentrations of 4 mg/L, 8 mg/L, and 12 mg/L). Following the end of the treatment, behavioral tests (Y maze test, Novel tank test) were conducted on the zebrafish, and the biochemical (MDA, Catalase, SOD, GSH) and molecular parameters (AchE, Iron levels, IL-1ß, TNF-α, CDK-5, GSK-3ß, and NLRP3) of the zebrafish brain were also assessed. In the novel tank test, emoxypine succinate-treated groups exhibited significantly increased time in the upper zone (p < 0.001), higher distance travelled (p < 0.001), and shorter latency to the top (p < 0.001) compared to the negative control. Similarly, the Y-maze test revealed improved time in the novel arm (p < 0.001) and total distance travelled (p < 0.001) in treated groups versus the negative control. Assessment of oxidative stress parameters demonstrated significant reductions in oxidative stress in emoxypine succinate-treated groups. Furthermore, AChE activity decreased significantly (p < 0.001), and brain iron levels decreased substantially (p < 0.001) in treated groups, indicating positive therapeutic outcomes. Molecular analysis showed a significant reduction in pro-inflammatory markers like IL-1ß, TNF-α, CDK-5, GSK-3ß, and NLRP3 (p < 0.001). This comprehensive study highlights the potential efficacy of emoxypine succinate in mitigating neurodegeneration associated with iron dysregulation.

Reversibility of cognitive worsening observed with BACE inhibitor umibecestat in the Alzheimer's Prevention Initiative (API) Generation Studies.

INTRODUCTION: The Alzheimer's Prevention Initiative (API) Generation Studies evaluated the BACE inhibitor umibecestat for Alzheimer's disease (AD) prevention. The studies were terminated early, and the reversibility of umibecestat's side effects was assessed. METHODS: Cognitively unimpaired 60- to 75-year-old apolipoprotein E (APOE) Îµ4 homozygotes and heterozygotes (the latter with elevated brain amyloid deposition) (n = 1556) received umibecestat (50 or 15 mg daily) or placebo for 7 months on average and were followed for a median (interquartile range) of 4 (3 to 6) months after washout. RESULTS: Compared to placebo, umibecestat-treated participants had small, non-progressive, but statistically significant decline in performance on certain cognitive batteries including Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and API Preclinical Composite Cognitive test, but not Clinical Dementia Rating-Sum of Boxes. RBANS differences were no longer significant at the end of follow-up. DISCUSSION: In people at genetic risk for AD, high-dose beta-site amyloid precursor protein cleaving enzyme (BACE) inhibition was associated with early mild cognitive worsening, which reversed shortly after washout, suggesting a symptomatic side effect not associated with neurodegeneration. Fully anonymized data, images, and samples are available upon request for further research on BACE inhibition. HIGHLIGHTS: This is the first trial with blinded assessment of reversibility of BACE inhibitor side effects. Umibecestat was tested in cognitively unimpaired persons at genetic risk for AD. Umibecestat led to early mild cognitive decline that reversed shortly after washout. This suggests a potentially manageable effect not associated with neurodegeneration. Further research may determine the future of BACE inhibition in AD prevention.

MEDI1814 selectively reduces free Aß42 in cerebrospinal fluid of non-clinical species and Alzheimer's disease patients.

INTRODUCTION: Small molecules and antibodies are being developed to lower amyloid beta (Aß) peptides. METHODS: We describe MEDI1814, a fully human high-affinity monoclonal antibody selective for Aß42, the pathogenic self-aggregating species of Aß. RESULTS: MEDI1814 reduces free Aß42 without impacting Aß40 in the cerebrospinal fluid of rats and cynomolgus monkeys after systemic administration. MEDI1814 administration to patients with Alzheimer's disease (AD; n = 57) in single or repeat doses up to 1800 mg intravenously or 200 mg subcutaneously was associated with a favorable safety and tolerability profile. No cases of amyloid-related imaging abnormalities were observed. Predictable dose-proportional changes in serum exposures for MEDI1814 were observed across cohorts. Cerebrospinal fluid (CSF) analysis demonstrated central nervous system penetration of MEDI1814. Pharmacodynamic data showed dose-dependent suppression of free Aß42, increases in total (bound and free) Aß42, but no change in total Aß40 in CSF across doses. DISCUSSION: MEDI1814 offers a differentiated approach to impacting Aß in AD via selective reduction of free Aß42.

Unveiling the theranostic potential of SPIONs in Alzheimer's disease management.

Alzheimer's disease (AD) is a devastating kind of dementia that is becoming more common worldwide. Toxic amyloid-beta (Aß) aggregates are the primary cause of AD onset and development. Superparamagnetic iron oxide nanoparticles (SPIONs) have received a lot of interest in AD therapy over the last decade because of their ability to redirect the Aß fibrillation process and improve associated brain dysfunction. The potential diagnostic application of SPIONs in AD has dramatically increased this interest. Furthermore, surface-modified engineered SPIONs function as drug carriers to improve the efficacy of current therapies. Various preclinical and clinical studies on the role of SPIONs in AD pathology have produced encouraging results. However, due to their physicochemical properties (e.g., size, surface charge, and particle concentration) in the biological milieu, SPIONs may play the role of a preventive or accelerative agent in AD. Even though SPIONs are potential therapeutic and diagnostic options in AD, significant efforts are still needed to overcome the inconsistencies and safety concerns. This review evaluated the current understanding of how various SPIONs interact with AD models and explored the discrepancies in their efficacy and safety.

Predictors of prognosis in Alzheimer's disease: The role of cognitive dysfunction, immune abnormalities, and advanced neuroimaging.

Alzheimer's disease (AD) is a grave illness that results in cognitive and social issues. A recent study examined the association between neuroimaging results, cognitive dysfunction, atypical cellular immune function, and poor prognostic factors in AD patients who demonstrated poor prognosis. Poor prognosis was associated with abnormal cellular immune function, extrapyramidal symptoms, altered consciousness, abnormal electroencephalogram, modified Rankin scale, increased neutrophil lymphocyte ratio, and severe pneumonia. The impaired cellular immune function characterized by a reduction in the blood T lymphocytes' proportion predicted poor prognosis as an independent risk factor in AD. Early initiation and maintenance of AD medications is associated with better outcomes.

Exploring the nexus of cGAS STING pathway in neurodegenerative terrain: A therapeutic odyssey.

By detecting and responding to cytosolic DNA, the cGAS STING pathway regulates the innate immune responses bymediatinginflammatory reactions and antiviral defense. Thederegulation and modification of this system have been linked to variousneurodegenerative diseases like AD, PD and ALS. Accumulation of tau protein and Aß aggregates to activate the pathway and releases neuroinflammatory cytokines which accelerates neuronal dysfunction and cognitive impairment as the symptom of AD. Similarly, in PD Alpha-synuclein aggregates activate the cGAS STING pathway and regulate the neuroinflammation and oxidative stress. In ALS, mutation of the genes causes the activation of the pathway which leads to motor neuron degeneration. Alteration of the cGAS STING pathway also leads to mitochondrial dysfunction and impaired autophagy. Preclinical investigations of AD, PD, and ALS animal models showed that STING pathway inhibitors reduced inflammation and improved neurological outcomes and modulators of the cGAS STING pathway may treat these neurodegenerative disorders. In this review we focus on the fact thatneuroinflammation, neuronal dysfunction, and various disease progressions can be treated byaltering the cGAS STING pathway. Understanding the processes and creating specific interventions for this route may offer new treatments for these terrible illnesses.

A streamlined, resource-efficient immunoprecipitation-mass spectrometry method for quantifying plasma amyloid-ß biomarkers in Alzheimer's disease.

High-performance, resource-efficient methods for plasma amyloid-ß (Aß) quantification in Alzheimer's disease are lacking; existing mass spectrometry-based assays are resource- and time-intensive. We developed a streamlined mass spectrometry method with a single immunoprecipitation step, an optimized buffer system, and ≤75% less antibody requirement. Analytical and clinical performances were compared with an in-house reproduced version of a well-known two-step assay. The streamlined assay showed high dilution linearity (r2>0.99) and precision (< 10% coefficient of variation), low quantification limits (Aß1-40: 12.5 pg/ml; Aß1-42: 3.125 pg/ml), and high signal correlation (r2~0.7) with the two-step immunoprecipitation assay. The novel single-step assay showed more efficient recovery of Aß peptides via fewer immunoprecipitation steps, with significantly higher signal-to-noise ratios, even at plasma sample volumes down to 50 pl. Both assays had equivalent performances in distinguishing non-elevated vs. elevated brain Aß-PET individuals. The new method enables simplified yet robust evaluation of plasma Aß biomarkers in Alzheimer's disease.

The Antiproteinopathy, Antioxidant, and Antiapoptotic Effects of Methylene Blue and 4-Phenylbutyric Acid Alone, and in Combination on Familial Alzheimer's Disease PSEN1 I416T Cholinergic-Like Neurons.

Familial Alzheimer's disease (FAD) is a chronic neurological condition that progresses over time. Currently, lacking a viable treatment, the use of multitarget medication combinations has generated interest as a potential FAD therapy approach. In this study, we examined the effects of 4-phenylbutyric acid (4-PBA) and methylene blue (MB) either separately or in combination on PSEN1 I416T cholinergic-like neuron cells (ChLNs), which serve as a model for FAD. We found that MB was significantly efficient at reducing the accumulation of intracellular Aß, phosphorylation of TAU Ser202/Thr205, and increasing Δψm, whereas 4-PBA was significantly efficient at diminishing oxidation of DJ-1Cys106-SH, expression of TP53, and increasing ACh-induced Ca2+ influx. Both agents were equally effective at blunting phosphorylated c-JUN at Ser63/Ser73 and activating caspase 3 (CASP3) into cleaved caspase 3 (CC3) on mutant cells. Combination of MB and 4-PBA at middle (0.1, 1) concentration significantly reduced iAß, p-TAU, and oxDJ-1 and augmented the ACh-induced Ca2+ influx compared to combined agents at low (0.05, 0.5) or high (0.5, 5) concentration. However, combined MB and 4-PBA were efficient only at dropping DJ-1Cys106-SO3 and increasing ACh-induced Ca2+ inward in mutant ChLNs. Our data show that the reagents MB and 4-PBA alone possess more than one action (e.g., antiamyloid, antioxidant, anti-TAU, antiapoptotic, and ACh-induced Ca2+ influx enhancers), that in combination might cancel or diminish each other. Together, these results strongly argue that MB and 4-PBA might protect PSEN1 I416T ChLNs from Aß-induced toxicity by working intracellularly as anti-Aß and anti-Tau agents, improving Δψm and cell survival, and extracellularly, by increasing ACh-induced Ca2+ ion influx. MB and 4-PBA are promising drugs with potential for repurposing in familial AD.