The efficacy and safety of lecanemab 10 mg/kg biweekly compared to a placebo in patients with Alzheimer's disease: a systematic review and meta-analysis of randomized controlled trials.

Alzheimer's disease, prevalent in individuals aged 60 and above, constitutes most dementia cases and significantly impairs memory and cognitive functions. With global Alzheimer's cases projected to triple by 2050, there is a pressing need for effective interventions. Lecanemab, a monoclonal antibody targeting amyloid-beta plaques, shows promise in slowing Alzheimer's progression. Positive clinical trial results have instilled hope in patients, prompting ongoing research to advance understanding and intervention possibilities. To contribute to this knowledge base, we conducted a systematic review and meta-analysis, focusing on lecanemab's efficacy and safety at a dosage of 10 mg/kg. This comprehensive approach aimed to address gaps in the current literature, scrutinize research disparities, and guide future investigations. Applying strict inclusion/exclusion criteria, we assessed study details, participant information, and intervention specifics, using the Cochrane risk of bias tool for quality evaluation. Statistical analyses, conducted with R software, included risk ratios and mean differences, assessing heterogeneity and publication bias. The meta-analysis reveals a significant positive effect of lecanemab (10 mg/kg biweekly) on cognitive outcomes in Alzheimer's disease. Consistent reductions in ADCOMS, CDR-SB, and ADAS-cog14 scores across studies indicate drug efficacy with narrow confidence intervals and no significant heterogeneity. While TEAE shows no significant difference, heightened risks of ARIA-E and ARIA-H associated with lecanemab underscore the need for vigilant safety monitoring in clinical practice. Despite the drug efficacy, the study emphasizes a balanced assessment of benefits and potential risks associated with lecanemab, providing critical insights for clinicians evaluating its use in addressing cognitive impairment in individuals with Alzheimer's disease.

The role of PIMT in Alzheimer's disease pathogenesis: A novel hypothesis.

There are multiple theories of Alzheimer's disease pathogenesis. One major theory is that oxidation of amyloid beta (Aß) promotes plaque deposition that directly contributes to pathology. A competing theory is that hypomethylation of DNA (due to altered one carbon metabolism) results in pathology through altered gene regulation. Herein, we propose a novel hypothesis involving L-isoaspartyl methyltransferase (PIMT) that unifies the Aß and DNA hypomethylation hypotheses into a single model. Importantly, the proposed model allows bidirectional regulation of Aß oxidation and DNA hypomethylation. The proposed hypothesis does not exclude simultaneous contributions by other mechanisms (e.g., neurofibrillary tangles). The new hypothesis is formulated to encompass oxidative stress, fibrillation, DNA hypomethylation, and metabolic perturbations in one carbon metabolism (i.e., methionine and folate cycles). In addition, deductive predictions of the hypothesis are presented both to guide empirical testing of the hypothesis and to provide candidate strategies for therapeutic intervention and/or nutritional modification. HIGHLIGHTS: PIMT repairs L-isoaspartyl groups on amyloid beta and decreases fibrillation. SAM is a common methyl donor for PIMT and DNA methyltransferases. Increased PIMT activity competes with DNA methylation and vice versa. The PIMT hypothesis bridges a gap between plaque and DNA methylation hypotheses.

An Activatable NIR-II Fluorescent Reporter for In Vivo Imaging of Amyloid-ß Plaques.

Fluorescence imaging in the second near-infrared (NIR-II) window holds great promise for in vivo visualization of amyloid-ß (Aß) pathology, which can facilitate characterization and deep understanding of Alzheimer's disease (AD); however, it has been rarely exploited. Herein, we report the development of NIR-II fluorescent reporters with a donor-π-acceptor (D-π-A) architecture for specific detection of Aß plaques in AD-model mice. Among all the designed probes, DMP2 exhibits the highest affinity to Aß fibrils and can specifically activate its NIR-II fluorescence after binding to Aß fibrils via suppressed twisted intramolecular charge transfer (TICT) effect. With suitable lipophilicity for ideal blood-brain barrier (BBB) penetrability and deep-tissue penetration of NIR-II fluorescence, DMP2 possesses specific detection of Aß plaques in in vivo AD-model mice. Thus, this study presents a potential agent for non-invasive imaging of Aß plaques and deep deciphering of AD progression.

Lysosomal enzyme tripeptidyl peptidase 1 destabilizes fibrillar Aß by multiple endoproteolytic cleavages within the ß-sheet domain.

Accumulation of amyloid-beta (Aß), which is associated with Alzheimer's disease, can be caused by excess production or insufficient clearance. Because of its ß-sheet structure, fibrillar Aß is resistant to proteolysis, which would contribute to slow degradation of Aß plaques in vivo. Fibrillar Aß can be internalized by microglia, which are the scavenger cells of the brain, but the fibrils are degraded only slowly in microglial lysosomes. Cathepsin B is a lysosomal protease that has been shown to proteolyze fibrillar Aß. Tripeptidyl peptidase 1 (TPP1), a lysosomal serine protease, possesses endopeptidase activity and has been shown to cleave peptides between hydrophobic residues. Herein, we demonstrate that TPP1 is able to proteolyze fibrillar Aß efficiently. Mass spectrometry analysis of peptides released from fibrillar Aß digested with TPP1 reveals several endoproteolytic cleavages including some within ß-sheet regions that are important for fibril formation. Using molecular dynamics simulations, we demonstrate that these cleavages destabilize fibrillar ß-sheet structure. The demonstration that TPP1 can degrade fibrillar forms of Aß provides insight into the turnover of fibrillar Aß and may lead to new therapeutic methods to increase degradation of Aß plaques.

Impairment of Spike-Timing-Dependent Plasticity at Schaffer Collateral-CA1 Synapses in Adult APP/PS1 Mice Depends on Proximity of Aß Plaques.

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder characterized by progressive and irreversible cognitive decline, with no disease-modifying therapy until today. Spike timing-dependent plasticity (STDP) is a Hebbian form of synaptic plasticity, and a strong candidate to underlie learning and memory at the single neuron level. Although several studies reported impaired long-term potentiation (LTP) in the hippocampus in AD mouse models, the impact of amyloid-ß (Aß) pathology on STDP in the hippocampus is not known. Using whole cell patch clamp recordings in CA1 pyramidal neurons of acute transversal hippocampal slices, we investigated timing-dependent (t-) LTP induced by STDP paradigms at Schaffer collateral (SC)-CA1 synapses in slices of 6-month-old adult APP/PS1 AD model mice. Our results show that t-LTP can be induced even in fully developed adult mice with different and even low repeat STDP paradigms. Further, adult APP/PS1 mice displayed intact t-LTP induced by 1 presynaptic EPSP paired with 4 postsynaptic APs (6× 1:4) or 1 presynaptic EPSP paired with 1 postsynaptic AP (100× 1:1) STDP paradigms when the position of Aß plaques relative to recorded CA1 neurons in the slice were not considered. However, when Aß plaques were live stained with the fluorescent dye methoxy-X04, we observed that in CA1 neurons with their somata <200 µm away from the border of the nearest Aß plaque, t-LTP induced by 6× 1:4 stimulation was significantly impaired, while t-LTP was unaltered in CA1 neurons >200 µm away from plaques. Treatment of APP/PS1 mice with the anti-inflammatory drug fingolimod that we previously showed to alleviate synaptic deficits in this AD mouse model did not rescue the impaired t-LTP. Our data reveal that overexpression of APP and PS1 mutations in AD model mice disrupts t-LTP in an Aß plaque distance-dependent manner, but cannot be improved by fingolimod (FTY720) that has been shown to rescue conventional LTP in CA1 of APP/PS1 mice.

APOE genotype-dependent pharmacogenetic responses to rapamycin for preventing Alzheimer's disease.

The ε4 allele of Apolipoprotein (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD), the most common form of dementia. Cognitively normal APOE4 carriers have developed amyloid beta (Aß) plaques and cerebrovascular, metabolic and structural deficits decades before showing the cognitive impairment. Interventions that can inhibit Aß retention and restore the brain functions to normal would be critical to prevent AD for the asymptomatic APOE4 carriers. A major goal of the study was to identify the potential usefulness of rapamycin (Rapa), a pharmacological intervention for extending longevity, for preventing AD in the mice that express human APOE4 gene and overexpress Aß (the E4FAD mice). Another goal of the study was to identify the potential pharmacogenetic differences in response to rapamycin between the E4FAD and E3FAD mice, the mice with human APOE ε3 allele. We used multi-modal MRI to measure in vivo cerebral blood flow (CBF), neurotransmitter levels, white matter integrity, water content, cerebrovascular reactivity (CVR) and somatosensory response; used behavioral assessments to determine cognitive function; used biochemistry assays to determine Aß retention and blood-brain barrier (BBB) functions; and used metabolomics to identify brain metabolic changes. We found that in the E4FAD mice, rapamycin normalized bodyweight, restored CBF (especially in female), BBB activity for Aß transport, neurotransmitter levels, neuronal integrity and free fatty acid level, and reduced Aß retention, which were not observe in the E3FAD-Rapa mice. In contrast, E3FAD-Rapa mice had lower CVR responses, lower anxiety and reduced glycolysis in the brain, which were not seen in the E4FAD-Rapa mice. Further, rapamycin appeared to normalize lipid-associated metabolism in the E4FAD mice, while slowed overall glucose-associated metabolism in the E3FAD mice. Finally, rapamycin enhanced overall water content, water diffusion in white matter, and spatial memory in both E3FAD and E4FAD mice, but did not impact the somatosensory responses under hindpaw stimulation. Our findings indicated that rapamycin was able to restore brain functions and reduce AD risk for young, asymptomatic E4FAD mice, and there were pharmacogenetic differences between the E3FAD and E4FAD mice. As the multi-modal MRI methods used in the study are readily to be used in humans and rapamycin is FDA-approved, our results may pave a way for future clinical testing of the pharmacogenetic responses in humans with different APOE alleles, and potentially using rapamycin to prevent AD for asymptomatic APOE4 carriers.

Probing amyloid-ß pathology in transgenic Alzheimer's disease (tgArcSwe) mice using MALDI imaging mass spectrometry.

The pathological mechanisms underlying Alzheimer's disease (AD) are still not understood. The disease pathology is characterized by the accumulation and aggregation of amyloid-ß (Aß) peptides into extracellular plaques, however the factors that promote neurotoxic Aß aggregation remain elusive. Imaging mass spectrometry (IMS) is a powerful technique to comprehensively elucidate the spatial distribution patterns of lipids, peptides and proteins in biological tissues. In the present study, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS)-based imaging was used to study Aß deposition in transgenic mouse brain tissue and to elucidate the plaque-associated chemical microenvironment. The imaging experiments were performed in brain sections of transgenic Alzheimer's disease mice carrying the Arctic and Swedish mutation of amyloid-beta precursor protein (tgArcSwe). Multivariate image analysis was used to interrogate the IMS data for identifying pathologically relevant, anatomical features based on their chemical identity. This include cortical and hippocampal Aß deposits, whose amyloid peptide content was further verified using immunohistochemistry and laser microdissection followed by MALDI MS analysis. Subsequent statistical analysis on spectral data of regions of interest revealed brain region-specific differences in Aß peptide aggregation. Moreover, other plaque-associated protein species were identified including macrophage migration inhibitory factor suggesting neuroinflammatory processes and glial cell reactivity to be involved in AD pathology. The presented data further highlight the potential of IMS as a powerful approach in neuropathology. Hanrieder et al. described an imaging mass spectrometry based study on comprehensive spatial profiling of C-terminally truncated Aß species within individual plaques in tgArcSwe mice. Here, brain region-dependent differences in Aß truncation and other plaque-associated proteins, such as macrophage migration inhibitory factor, were observed. The data shed further light on plaque-associated molecular mechanisms implicated in Alzheimer's pathogenesis. Cover image for this issue: doi: 10.1111/jnc.13328.

A Comprehensive Review of Membrane Transporters and MicroRNA Regulation in Alzheimer's Disease.

Alzheimer's disease (AD) is a distressing neurodegenerative condition characterized by the accumulation of amyloid-beta (Aß) plaques and tau tangles within the brain. The interconnectedness between membrane transporters (SLCs) and microRNAs (miRNAs) in AD pathogenesis has gained increasing attention. This review explores the localization, substrates, and functions of SLC transporters in the brain, emphasizing the roles of transporters for glutamate, glucose, nucleosides, and other essential compounds. The examination delves into the significance of SLCs in AD, their potential for drug development, and the intricate realm of miRNAs, encompassing their transcription, processing, functions, and regulation. MiRNAs have emerged as significant players in AD, including those associated with mitochondria and synapses. Furthermore, this review discusses the intriguing nexus of miRNAs targeting SLC transporters and their potential as therapeutic targets in AD. Finally, the review underscores the interaction between SLC transporters and miRNA regulation within the context of Alzheimer's disease, underscoring the need for further research in this area. This comprehensive review aims to shed light on the complex mechanisms underlying the causation of AD and provides insights into potential therapeutic approaches.

Microglial Piezo1 mechanosensitive channel as a therapeutic target in Alzheimer's disease.

Microglia are the resident macrophages of the central nervous system (CNS) that control brain development, maintain neural environments, respond to injuries, and regulate neuroinflammation. Despite their significant impact on various physiological and pathological processes across mammalian biology, there remains a notable gap in our understanding of how microglia perceive and transmit mechanical signals in both normal and diseased states. Recent studies have revealed that microglia possess the ability to detect changes in the mechanical properties of their environment, such as alterations in stiffness or pressure. These changes may occur during development, aging, or in pathological conditions such as trauma or neurodegenerative diseases. This review will discuss microglial Piezo1 mechanosensitive channels as potential therapeutic targets for Alzheimer's disease (AD). The structure, function, and modulation of Piezo1 will be discussed, as well as its role in facilitating microglial clearance of misfolded amyloid-ß (Aß) proteins implicated in the pathology of AD.

Human in vivo evidence of associations between herpes simplex virus and cerebral amyloid-beta load in normal aging.

BACKGROUND: Mounting data suggests that herpes simplex virus type 1 (HSV-1) is involved in the pathogenesis of AD, possibly instigating amyloid-beta (Aß) accumulation decades before the onset of clinical symptoms. However, human in vivo evidence linking HSV-1 infection to AD pathology is lacking in normal aging, which may contribute to the elucidation of the role of HSV-1 infection as a potential AD risk factor. METHODS: To shed light into this question, serum anti-HSV IgG levels were correlated with 18F-Florbetaben-PET binding to Aß deposits and blood markers of neurodegeneration (pTau181 and neurofilament light chain) in cognitively normal older adults. Additionally, we investigated whether associations between anti-HSV IgG and AD markers were more evident in APOE4 carriers. RESULTS: We showed that increased anti-HSV IgG levels are associated with higher Aß load in fronto-temporal regions of cognitively normal older adults. Remarkably, these cortical regions exhibited abnormal patterns of resting state-functional connectivity (rs-FC) only in those individuals showing the highest levels of anti-HSV IgG. We further found that positive relationships between anti-HSV IgG levels and Aß load, particularly in the anterior cingulate cortex, are moderated by the APOE4 genotype, the strongest genetic risk factor for AD. Importantly, anti-HSV IgG levels were unrelated to either subclinical cognitive deficits or to blood markers of neurodegeneration. CONCLUSIONS: All together, these results suggest that HSV infection is selectively related to cortical Aß deposition in normal aging, supporting the inclusion of cognitively normal older adults in prospective trials of antimicrobial therapy aimed at decreasing the AD risk in the aging population.

Recent Advances in Drug Delivery Systems Targeting Insulin Signalling for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of neurofibrillary tangles and amyloid-ß plaques. Recent research has unveiled the pivotal role of insulin signaling dysfunction in the pathogenesis of AD. Insulin, once thought to be unrelated to brain function, has emerged as a crucial factor in neuronal survival, synaptic plasticity, and cognitive processes. Insulin and the downstream insulin signaling molecules are found mainly in the hippocampus and cortex. Some molecules responsible for dysfunction in insulin signaling are GSK-3ß, Akt, PI3K, and IRS. Irregularities in insulin signaling or insulin resistance may arise from changes in the phosphorylation levels of key molecules, which can be influenced by both stimulation and inactivity. This, in turn, is believed to be a crucial factor contributing to the development of AD, which is characterized by oxidative stress, neuroinflammation, and other pathological hallmarks. Furthermore, this route is known to be indirectly influenced by Nrf2, NF-κB, and the caspases. This mini-review delves into the intricate relationship between insulin signaling and AD, exploring how disruptions in this pathway contribute to disease progression. Moreover, we examine recent advances in drug delivery systems designed to target insulin signaling for AD treatment. From oral insulin delivery to innovative nanoparticle approaches and intranasal administration, these strategies hold promise in mitigating the impact of insulin resistance on AD. This review consolidates current knowledge to shed light on the potential of these interventions as targeted therapeutic options for AD.

Revisiting the focal role of endostatin and environmental factors in Alzheimer's disease.

Alzheimer's disease (AD) is a condition initiated by the assimilation of ß-amyloid plaques (Aß) and tau tangles, leading to neurodegeneration. It involves frequently cognitive decline as well as memory impairment in patients. Efforts in therapeutic interventions are currently facing challenges in identifying targets within this scaffold that can significantly alter the clinical course for individuals with AD. Moreover, in AD, neurons release a protein called endostatin, which accumulates in Aß plaques and enhances AD. This accumulation of Aß in the triggers a cascade of events leading to synaptic dysfunction, neuroinflammation, and ultimately neuronal death. Environmental factors nowadays increase the risk of AD with prolonged exposure of heavy metals such as copper (Cu), lead (Pb), mercury (Hg), cadmium (Cd), and other pesticides. It has been observed that these factors can cause the aggregation of Aß and tau which initiates the plaque formation and hence leads to enhanced pathogenesis of AD. This review summarizes the interlinking between heavy metals, environmental factors, pesticides, endostatin, and progression of AD has been deliberated with recent findings.

Alzheimer's Disease: Exploring the Landscape of Cognitive Decline.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. The pathology of AD is marked by the accumulation of amyloid beta plaques and tau protein tangles in the brain, along with neuroinflammation and synaptic dysfunction. Genetic factors, such as mutations in APP, PSEN1, and PSEN2 genes, as well as the APOE ε4 allele, contribute to increased risk of acquiring AD. Currently available treatments provide symptomatic relief but do not halt disease progression. Research efforts are focused on developing disease-modifying therapies that target the underlying pathological mechanisms of AD. Advances in identification and validation of reliable biomarkers for AD hold great promise for enhancing early diagnosis, monitoring disease progression, and assessing treatment response in clinical practice in effort to alleviate the burden of this devastating disease. In this paper, we analyze data from the CAS Content Collection to summarize the research progress in Alzheimer's disease. We examine the publication landscape in effort to provide insights into current knowledge advances and developments. We also review the most discussed and emerging concepts and assess the strategies to combat the disease. We explore the genetic risk factors, pharmacological targets, and comorbid diseases. Finally, we inspect clinical applications of products against AD with their development pipelines and efforts for drug repurposing. The objective of this review is to provide a broad overview of the evolving landscape of current knowledge regarding AD, to outline challenges, and to evaluate growth opportunities to further efforts in combating the disease.

Passive Anti-amyloid Beta Monoclonal Antibodies: Lessons Learned over Past 20 Years.

Alzheimer's disease (AD) is a neurodegenerative disorder that significantly impairs cognitive and functional abilities, placing a substantial burden on both patients and caregivers. Current symptomatic treatments fail to halt the progression of AD, highlighting the urgent need for more effective disease-modifying therapies (DMTs). DMTs under development are classified as either passive or active on the basis of their mechanisms of eliciting an immune response. While this review will touch on active immunotherapies, we primarily focus on anti-amyloid beta monoclonal antibodies (mAbs), a form of passive immunotherapy, discussing their multifaceted role in AD treatment and the critical factors influencing their therapeutic efficacy. With two mAbs now approved and prescribed in the clinical setting, it is crucial to reflect on the lessons learned from trials of earlier mAbs that have shaped their development and contributed to their current success. These insights can then guide the creation of even more effective mAbs, ultimately enhancing therapeutic outcomes for patients with AD while minimizing adverse events.

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.

Disease and brain region specific immune response profiles in neurodegenerative diseases with pure and mixed protein pathologies.

The disease-specific accumulation of pathological proteins has long been the major focus of research in neurodegenerative diseases (ND), including Alzheimer's disease (AD) and related dementias (RD), but the recent identification of a multitude of genetic risk factors for ND in immune-associated genes highlights the importance of immune processes in disease pathogenesis and progression. Studies in animal models have characterized the local immune response to disease-specific proteins in AD and ADRD, but due to the complexity of disease processes and the co-existence of multiple protein pathologies in human donor brains, the precise role of immune processes in ND is far from understood. To better characterize the interplay between different extracellular and intracellular protein pathologies and the brain's intrinsic immune system in ND, we set out to comprehensively profile the local immune response in postmortem brain samples of individuals with "pure" beta-Amyloid and tau pathology (AD), "pure" α-Synuclein pathology in Lewy body diseases (LBD), as well as cases with Alzheimer's disease neuropathological changes (ADNC) and Lewy body pathology (MIX). Combining immunohistochemical profiling of microglia and digital image analysis, along with deep immunophenotyping using gene expression profiling on the NanoString nCounter® platform and digital spatial profiling on the NanoString GeoMx® platform we identified a robust immune activation signature in AD brain samples. This signature is maintained in persons with mixed pathologies, irrespective of co-existence of AD pathology and Lewy body (LB) pathology, while LBD brain samples with "pure" LB pathology exhibit an attenuated and distinct immune signature. Our studies highlight disease- and brain region-specific immune response profiles to intracellular and extracellular protein pathologies and further underscore the complexity of neuroimmune interactions in ND.

Advancing Alzheimer's Research With Zebrafish Models: Current Insights, Addressing Challenges, and Charting Future Courses.

Alzheimer's disease (AD) is a neurological condition that progressively impairs cognitive function and results in memory loss. Despite substantial research efforts, little is known about the specific processes driving AD, and there are few proven therapies. Because of their physiological and genetic resemblance to humans, zebrafish (Danio rerio) have become an important model organism for furthering research on AD. This abstract discusses the difficulties faced, looks at the insights currently garnered from zebrafish models, and suggests future research options. AD knowledge has greatly benefited from the use of zebrafish models. Transgenic zebrafish that express human AD-associated genes, such as tau and amyloid precursor protein (APP), display tau neurofibrillary tangles (NFTs) and amyloid-beta (Aß) plaques, two of the disease's main clinical characteristics. These models have clarified the roles of oxidative stress, inflammation, and calcium homeostasis in the course of AD and allowed for the purpose of high-throughput screening of potential therapeutic agents. Understanding the growth and deterioration of neurons has been greatly aided by real-time zebrafish imaging. Fully using zebrafish models in AD research requires addressing a number of issues. The dissimilarities in zebrafish anatomy and physiology from humans, the difficulty of developing models that replicate progressive and late-onset AD (LOAD), and the requirement for standardized procedures to evaluate alterations in zebrafish cognition and behavior are a few issues. Furthermore, variations in the genetic makeup of zebrafish strains might affect the results of experiments. Future directions include developing standardized behavioral assays and cognitive tests, working together to create extensive databases of zebrafish genetic and phenotypic data, and using genetic engineering techniques like CRISPR/Cas9 to create more complex zebrafish models. Combining zebrafish models with other model species helps expedite the conversion of research results into therapeutic applications and offers a more thorough knowledge of AD. To sum up, zebrafish models have made a substantial contribution to Alzheimer's research by offering insightful information on the causes of the illness and possible therapies. By tackling present issues and formulating a planned future path, we can improve the use of zebrafish to decipher the mysteries of Alzheimer's and help create successful treatments.

A Review of the Retinal Impact of Traumatic Brain Injury and Alzheimer's Disease: Exploring Inflammasome Complexes and Nerve Fiber Layer Alterations.

A huge number of new cases - around a few million of traumatic brain injury (TBI) - are recorded globally each year, making it a major public health risk. A significant portion of all accident-related deaths are attributable to TBI, a notable mortality rate. There are TBI deaths in every age range. Long-term neurobehavioral impacts, such as altered emotions and personalities, cognitive and mental deficits, and so on, are experienced by the majority of survivors. Our main objective is to understand the possible mechanism of the NLRP3 inflammasome in retinal neurons and enhance precision regarding reducing the burden of retinal neurodegeneration in TBI-induced AD. Both primary and secondary insults initiate the intricate pathophysiology of traumatic brain injury. Primary injuries are caused by mechanical force and occur right after the collision. Long-lasting and delayed secondary injuries follow. Studies demonstrating the continuous nature of research on the relationship between retinal neurons and TBI-induced Alzheimer's disease (AD) include neurodegeneration, retinal changes, and inflammatory response biomarkers. TBI can cause changes that resemble those seen in AD. This includes the accumulation of tau tangles and amyloid-beta plaques, which are also observed in the retina and imply a potential relationship between AD, traumatic brain injury, and retinal health. The linkage between TBI and AD, the effect of the innate immune system in post-TBI AD, the function of immunological moderators, the activation and assembly of inflammasomes in TBI, the pathophysiology of TBI, and the connection between TBI and inflammasome activity were the main topics of discussion in the following discussions. Of particular interest was the potential mechanism by which the NLRP3 inflammasome, in conjunction with SREBP2 and SCAP inflammasome, in retinal neurons in TBI-induced AD. The thinning of RNFL, poor lipid metabolism, and new developments such as drug delivery technologies, lipid metabolism modulation in retinal neurons, and drug-targeting lipid pathways and their mechanisms are then covered in this article.

NF-κB Pathway and Its Inhibitors: A Promising Frontier in the Management of Alzheimer's Disease.

The nuclear factor kappa B (NF-κB) pathway has emerged as a pivotal player in the pathogenesis of various diseases, including neurodegenerative illnesses like Alzheimer's disease (AD). The involvement of the NF-κB pathway in immune system responses, inflammation, oxidative stress, and neuronal survival highlights its significance in AD progression. We discuss the advantages of NF-κB pathway inhibition, including the potential to mitigate neuroinflammation, modulate amyloid beta (Aß) production, and promote neuronal survival. However, we also acknowledge the limitations and challenges associated with this approach. Balancing the fine line between dampening inflammation and preserving physiological immune responses is critical to avoid unintended consequences. This review combines current knowledge on the NF-κB pathway's intricate involvement in AD pathogenesis, emphasizing its potential as a therapeutic target. By evaluating both advantages and limitations, we provide a holistic view of the feasibility and challenges of NF-κB pathway modulation in AD treatment. As the quest for effective AD therapies continues, an in-depth understanding of the NF-κB pathway's multifaceted roles will guide the development of targeted interventions with the potential to improve AD management.

Inhibiting 5-hydroxytryptamine receptor 3 alleviates pathological changes of a mouse model of Alzheimer's disease.

Extracellular amyloid beta (Aß) plaques are main pathological feature of Alzheimer's disease. However, the specific type of neurons that produce Aß peptides in the initial stage of Alzheimer's disease are unknown. In this study, we found that 5-hydroxytryptamin receptor 3A subunit (HTR3A) was highly expressed in the brain tissue of transgenic amyloid precursor protein and presenilin-1 mice (an Alzheimer's disease model) and patients with Alzheimer's disease. To investigate whether HTR3A-positive interneurons are associated with the production of Aß plaques, we performed double immunostaining and found that HTR3A-positive interneurons were clustered around Aß plaques in the mouse model. Some amyloid precursor protein-positive or ß-site amyloid precursor protein cleaving enzyme-1-positive neurites near Aß plaques were co-localized with HTR3A interneurons. These results suggest that HTR3A -positive interneurons may partially contribute to the generation of Aß peptides. We treated 5.0-5.5-month-old model mice with tropisetron, a HTR3 antagonist, for 8 consecutive weeks. We found that the cognitive deficit of mice was partially reversed, Aß plaques and neuroinflammation were remarkably reduced, the expression of HTR3 was remarkably decreased and the calcineurin/nuclear factor of activated T-cell 4 signaling pathway was inhibited in treated model mice. These findings suggest that HTR3A interneurons partly contribute to generation of Aß peptide at the initial stage of Alzheimer's disease and inhibiting HTR3 partly reverses the pathological changes of Alzheimer's disease.