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Alzheimer’s disease (AD) is the most common type of dementia. Monoclonal antibodies (MABs) serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors, such as amyloid-β (Aβ) peptide, tau protein, and neuroinflammation. Specifically, based on their efficacy in removing Aβ plaques from the brains of patients with AD, the U.S. Food and Drug Administration has approved three anti-amyloid MABs, aducanumab (Aduhelm®), lecanemab (Leqembi®), and donanemab (Kisunla™). Notably, lecanemab received traditional approval after demonstrating clinical benefit, supporting the Aβ cascade hypothesis. These MABs targeting Aβ are categorized based on their affinity to diverse conformational features of Aβ, including monomer, fibril, protofibril, and plaque forms of Aβ as well as pyroglutamate Aβ. First-generation MABs targeting the non-toxic monomeric Aβ, such as solanezumab, bapineuzumab, and crenezumab, failed to demonstrate clinical benefit for AD in clinical trials. In contrast, second-generation MABs, including aducanumab, lecanemab, donanemab, and gantenerumab directed against pathogenic Aβ species and aggregates have shown that reducing Aβ deposition can be an effective strategy to slow cognitive impairment in AD. In this review, we provide a comprehensive overview of the current status, mechanisms, outcomes, and limitations of second-generation MABs for the clinical treatment of AD. Moreover, we discuss the perspectives and future directions of anti-amyloid MABs in the treatment of AD.

Alzheimer’s disease (AD) is not a single-cause disease; rather, it is a complex neurodegenerative disease involving multiple pathological pathways influenced by various risk factors. Aggregation and accumulation of amyloid beta (Aβ) and tau are the most prominent features in the brains of AD patients. Aggregated Aβ and tau exert neurotoxic effects in the central nervous system, contributing to the pathogenesis and progression of AD. They also act synergistically to cause neurodegeneration, resulting in memory loss. In this context, dual inhibition of Aβ and tau aggregation, or dissociation of these two aggregates, is considered promising for AD treatment. Recently, dual inhibitors capable of simultaneously targeting the aggregation and dissociation of both Aβ and tau have been investigated. Specific amino acid domains of Aβ and tau associated with their aggregation/dissociation have been identified. Subsequently, therapeutic agents that prevent aggregation or promote disaggregation by targeting these domains have been identified/developed. In this review, we summarize the major domains and properties involved in Aβ and tau aggregation, as well as the therapeutic effects and mechanisms of agents that simultaneously regulate their aggregation and dissociation. This comprehensive review may contribute to the design and discovery of next-generation dual-targeting drugs for Aβ and tau, potentially leading to the development of more effective therapeutic strategies for AD.

The orphan nuclear receptor Nurr1 (also known as NR4A2) is critical for the development and maintenance of midbrain dopaminergic neurons, and is associated with Parkinson's disease. However, an association between Nurr1 and Alzheimer's disease (AD)‐related pathology has not previously been reported. Here, we provide evidence that Nurr1 is expressed in a neuron‐specific manner in AD‐related brain regions; specifically, it is selectively expressed in glutamatergic neurons in the subiculum and the cortex of both normal and AD brains. Based on Nurr1’s expression patterns, we investigated potential functional roles of Nurr1 in AD pathology. Nurr1 expression was examined in the hippocampus and cortex of AD mouse model and postmortem human AD subjects. In addition, we performed both gain‐of‐function and loss‐of‐function studies of Nurr1 and its pharmacological activation in 5XFAD mice. We found that knockdown of Nurr1 significantly aggravated AD pathology while its overexpression alleviated it, including effects on Aβ accumulation, neuroinflammation, and neurodegeneration. Importantly, 5XFAD mice treated with amodiaquine, a highly selective synthetic Nurr1 agonist, showed robust reduction in typical AD features including deposition of Aβ plaques, neuronal loss, microgliosis, and impairment of adult hippocampal neurogenesis, leading to significant improvement of cognitive impairment. These in vivo and in vitro findings suggest that Nurr1 critically regulates AD‐related pathophysiology and identify Nurr1 as a novel AD therapeutic target.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment with amyloid-β (Aβ) accumulation, tau hyperphosphorylation, and neuroinflammation. Among these pathological features, microglial activation is hallmark of neuroinflammation. Chaga (Inonotus obliquus) extract has been traditionally used for its diverse pharmacological properties, including anti-inflammatory and neuroprotective effects. This study aimed to evaluate the therapeutic potential of INO10, an inotodiol-rich chaga extract, in murine BV2 microglial cells and a 3xTg-AD mouse model. In BV2 cells, INO10 significantly reduced LPS-induced expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), indicating its potent anti-inflammatory effects. Oral administration of INO10 significantly improved spatial memory in 3xTg-AD mice, as evidenced by increased spontaneous alternation in the Y-maze test. Furthermore, INO10 treatment attenuated neuroinflammation, as indicated by reduced microglial activation and downregulated expression of pro-inflammatory cytokines. In addition, immunohistochemical analysis confirmed that INO10 exhibited favorable bioavailability, supporting its potential as a neuroprotective agent. Histological analysis further revealed a reduction in Ab accumulation and tau phosphorylation in the hippocampus, accompanied by a marked decrease in neuroinflammatory markers. These findings suggest that INO10 effectively mitigates AD-related pathology by reducing Aβ deposition, tau hyperphosphorylation, and neuroinflammation, ultimately leading to cognitive enhancement. Given its multi-target neuroprotective properties, INO10 may serve as a promising natural compound for AD treatment. Further investigations are warranted to elucidate its precise mechanisms and clinical applicability.

Alzheimer’s disease (AD) is the most serious age-related neurodegenerative disease and causes destructive and irreversible cognitive decline. Failures in the development of therapeutics targeting amyloid-β (Aβ) and tau, principal proteins inducing pathology in AD, suggest a paradigm shift towards the development of new therapeutic targets. The gram-negative bacteria and lipopolysaccharides (LPS) are attractive new targets for AD treatment. Surprisingly, an altered distribution of gram-negative bacteria and their LPS has been reported in AD patients. Moreover, gram-negative bacteria and their LPS have been shown to affect a variety of AD-related pathologies, such as Aβ homeostasis, tau pathology, neuroinflammation, and neurodegeneration. Moreover, therapeutic approaches targeting gram-negative bacteria or gram-negative bacterial molecules have significantly alleviated AD-related pathology and cognitive dysfunction. Despite multiple evidence showing that the gram-negative bacteria and their LPS play a crucial role in AD pathogenesis, the pathogenic mechanisms of gram-negative bacteria and their LPS have not been clarified. Here, we summarize the roles and pathomechanisms of gram-negative bacteria and LPS in AD. Furthermore, we discuss the possibility of using gram-negative bacteria and gram-negative bacterial molecules as novel therapeutic targets and new pathological characteristics for AD.

Neuroinflammation, a key contributor to neurodegenerative diseases, results from excessive microglial activation. Microglia that respond to pathogenic molecules switch to the M1 type and secrete various immune cytokines, which can cause neuronal damage. Therefore, our study focused on molecules that can enhance the neuroprotective role of microglia and reduce neuronal damage. The adipocyte enhancer-binding protein 1 (AEBP1) gene is known for its role in regulating immune responses in macrophages. However, its role in neuroinflammation has not been fully explored. Therefore, we investigated the role of AEBP1 in microglial cells activated by lipopolysaccharide (LPS). First, we confirmed that AEBP1 is expressed in LPS-activated microglia and demonstrated that downregulation of AEBP1 using shRNA in activated microglia reduced the immune response via the nuclear factor-kappa-B (NFκB) pathway. These results promote a shift toward neuroprotective M2 microglia, thereby reducing neuronal damage. Next, we confirmed that the expression of AEBP1 was elevated in the brains of Alzheimer’s disease (AD) mice. Additionally, animal experiments to assess the therapeutic effects of AEBP1 showed that microglia gathered around amyloid beta (Aβ) and reduced its size. Taken together, our results provide the first evidence that AEBP1 can reduce inflammatory activity in microglia, suggesting its potential as a target molecule for immunotherapy.

Background/Objectives: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder for which no disease-modifying therapy that halts or substantially slows disease progression is currently available. Although antibody therapies targeting amyloid β (Aβ) have recently received FDA approval, their high cost, limited efficacy, and potential adverse effects highlight the need for alternative solutions. Therefore, the development of low-molecular-weight compounds capable of reducing toxic Aβ aggregates is of considerable interest. In this study, we investigated the effects of 2,3,4-trihydroxybenzophenone (THB) on the inhibition and disassembly of Aβ1–42 aggregates through in vitro and in vivo experiments. Methods: In vitro assays were performed to evaluate the effects of THB on Aβ1–42 aggregation and fibril disassembly. Cell viability assays and hippocampal slice electrophysiology were conducted to assess neurotoxicity and synaptic function. In vivo effects were examined in Aβ1–42 aggregate-injected mice and in 5 Familial AD mutations (5XFAD) mice using behavioral, histological, and electrophysiological analyses. Results: THB inhibited Aβ1–42 aggregation in a concentration-dependent manner and promoted the disassembly of preformed fibrils. THB attenuated Aβ1–42-induced Neuro2a cell death and restored Aβ1–42 aggregate-associated long-term potentiation (LTP) deficits in hippocampal slices. In Aβ1–42 aggregate-injected and 5XFAD mice, THB reduced amyloid pathology and neuroinflammatory markers and improved synaptic function and memory performance. Conclusions: These findings suggest that THB modulates pathogenic Aβ1–42 assemblies and provides a structural basis for the development of small-molecule modulators of Aβ1–42 aggregation with potential preventive or disease-modifying applications in AD.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline and neurodegeneration in the hippocampus. Despite the pathological importance of the hippocampal degeneration in AD, little topographical evidence exists of impaired hippocampal connectivity in patients with AD. To investigate the anatomical connections of the hippocampus, we injected the neurotracer 1,1′-dioctadecyl-3,3,3′3,3′-tetramethyl-indocarbocyanine perchlorate (DiI) into the hippocampi of 5XFAD mice, which were used as an animal model of AD. In wild-type controls, DiI-containing cells were found in the entorhinal cortex, medial septum, locus coeruleus, dorsal raphe, substantia nigra pars compacta, and olfactory bulb. Hippocampal inputs were decreased in multiple brain regions in the 5XFAD mice compared to wild-type littermate mice. These results are the first to reveal alterations at the cellular level in hippocampal connectivity in the brains of 5XFAD mice. These results suggest that anatomical mapping of hippocampal connectivity will elucidate new pathogenic mechanisms and therapeutic targets for AD treatment.

Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by irreversible cognitive decline. Senile plaques formed by amyloid-β (Aβ) peptides and neurofibrillary tangles, consisting of hyperphosphorylated tau protein accumulation, are prominent neuropathological features of AD. Impairment of adult neurogenesis is also a well-known pathology in AD. Adult neurogenesis is the process by which neurons are generated from adult neural stem cells. It is closely related to various functions, including cognition, as it occurs throughout life for continuous repair and development of specific neural pathways. Notably, subventricular zone (SVZ) neurogenesis, which occurs in the lateral ventricles, transports neurons to several brain regions such as the olfactory bulb, cerebral cortex, striatum, and hippocampus. These migrating neurons can affect cognitive function and behavior in different neurodegenerative diseases. Despite several studies indicating the importance of adult SVZ neurogenesis in neurodegenerative disorders, the pathological alterations and therapeutic implications of impaired adult neurogenesis in the SVZ in AD have not yet been fully explained. In this review, we summarize recent progress in understanding the alterations in adult SVZ neurogenesis in AD animal models and patients. Moreover, we discuss the potential therapeutic approaches for restoring impaired adult SVZ neurogenesis. Our goal is to impart to readers the importance of adult SVZ neurogenesis in AD and to provide new insights through the discussion of possible therapeutic approaches.

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles, which synergistically accelerate disease progression. Since Aβ plaques and tau tangles are key factors in the development of AD, dual-targeting of Aβ and tau aggregation represents a promising therapeutic strategy. Amodiaquine (AQ), a quinoline-based antimalarial, has recently attracted attention for its ability to suppress protein aggregation. However, direct effects of AQ on both Aβ and tau aggregation remain unclear. Methods: The effects of AQ on the aggregation and dissociation of Aβ and tau were examined using a thioflavin T (ThT) assays. Molecular docking and molecular dynamics (MD) simulations were performed to examine binding characteristics and structural interactions. The effects of AQ on the expression of pro-inflammatory cytokines induced by Aβ and tau aggregation in BV2 microglial cells were analyzed by qRT-PCR. Results: ThT assay demonstrated a dose-dependent dual effect of AQ on Aβ, where 25 μM inhibited aggregation after 36 h, while 250 μM markedly accelerated it, reaching a plateau within 12 h. All concentrations of AQ promoted the disassembly of mature Aβ fibrils within 12 h. Molecular docking revealed stronger binding of AQ to aggregated Aβ (−45.17 and −23.32 kcal/mol for pentameric 2BEG and hexameric 2NAO) than to monomeric Aβ (−4.81 and −7.29 kcal/mol for 1Z0Q and 2BEG). MD simulation suggested that AQ disrupted the cross-β-sheet interactions of Aβ aggregates. In the case of tau, ThT assay showed that all concentrations of AQ inhibited tau aggregation from 6 h, and 350 μM AQ promoted the disassembly of mature fibrils from 6 h. Molecular docking indicated stronger binding of AQ to aggregated tau (−27.95 and −12.13 kcal/mol for the pentameric and decameric 5O3L) than to monomeric tau (−3.05 kcal/mol for 8Q96). MD simulations revealed no major structural changes in the aggregates. In BV2 cells, 1 and 10 μM AQ significantly reduced Aβ and tau-induced TNF-α and IL-6 mRNA expressions. In APP-H4 cells, 10 μM AQ decreased the level of Aβ compared to the control. Conclusions: AQ modulates both Aβ and tau aggregation and attenuates neuroinflammation and reduces Aβ pathology, supporting its potential as a dual-target therapeutic candidate for AD.