Search Results (2,323)

Central lipid metabolism disorders are crucial for the development of Alzheimer’s disease (AD). Phlorizin (PHZ) improved lipid metabolism abnormalities in AD nematodes, but its mechanism of action in improving AD-related symptoms and whether it can alleviate AD cognitive impairment remain unclear. To elucidate the effects and mechanisms of PHZ on lipid metabolism disorders in an AD model, gavage administration of PHZ for 8 weeks improved cognitive dysfunction and lipid disorders in APPswe/PSEN1dE9 (APP/PS1) mice. Concurrently, in astrocytes induced by palmitic acid (PA)- mediated lipid metabolic disorder, PHZ treatment improved astrocytic lipid accumulation by upregulating the target peroxisome proliferator-activated receptor α (PPARα) and its downstream pathways, thereby promoting astrocytic fatty acid oxidation. We validated PHZ’s strong in vitro binding affinity with PPARα. Co-culture systems of lipid-metabolically disordered astrocytes and neurons further demonstrated that PHZ significantly improved neuronal cell viability and reduced intracellular lipid accumulation, thereby decreasing the expression of enzymes associated with β-amyloid protein (Aβ) production. This study demonstrates that gavage administration of PHZ for 2 months improves cognitive deficits and pathological markers in AD mice. Furthermore, at the cellular level, PHZ may exert its effects by enhancing astrocytic lipid metabolism, thereby preventing neuronal lipotoxicity and mitigating AD progression. Full article

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. Full article

Background/Objectives: Visual dysfunction emerges during the mild cognitive impairment stage of early Alzheimer’s disease (AD). While previous studies have primarily focused on retinal pathology, the early pathological progression across central nodes of the visual pathway remains inadequately characterized. This study examined regional pathological and structural alterations throughout the visual pathway at different disease stages in APP/PS1 transgenic mice aged 3, 6, and 9 months. Methods: Cognitive function was first assessed using novel object recognition and Y-maze tests to stage disease progression. Subsequently, Histological staining was employed to systematically analyze pathological features in the retina, lateral geniculate nucleus (LGN), and primary visual cortex (V1). Evaluated parameters encompassed β-amyloid (Aβ) deposition levels, microglial activation status, total neuronal counts, parvalbumin (PV)-positive neuron numbers, and tissue thickness measurements of the retina and V1. Results: At 6 months, mice exhibited an early symptomatic phenotype with selective spatial working memory deficits while long-term memory remained intact. Pathological analysis revealed concurrent Aβ deposition and microglial activation in V1, retina, and hippocampus by 6 months, whereas comparable LGN changes manifested only at 9 months, demonstrating regional heterogeneity in disease progression. V1 neuronal populations remained stable through 6 months but showed significant reduction by 9 months, though PV-positive neurons were selectively preserved. The LGN exhibited no neuronal loss even at 9 months. Gross structural thickness of both retina and V1 remained unchanged across all timepoints. Conclusions: These findings demonstrate that early visual system pathology in this AD model extends beyond the retina. The primary visual cortex exhibits early pathological changes (Aβ deposition and neuroinflammation) concurrent with hippocampal involvement, progressing to selective neuronal loss in later stages. The severity and selectivity of V1 pathology surpass those observed in other visual pathway nodes, including the LGN. Thus, V1 could represent not merely an affected region but a promising site for elucidating early cortical AD mechanisms and developing novel diagnostic biomarkers. Full article

Background: Hyperphosphorylated tau accumulation and neurofibrillary tangles (NFTs) are hallmarks of tauopathies, including Alzheimer’s disease (AD), and are strongly associated with cognitive decline. The rTg4510 mouse model, which expresses mutant human tau (P301L), develops progressive tauopathy in the absence of amyloid-β pathology, providing a valuable tool for investigating tau-driven neurodegeneration. Previous studies have demonstrated spatial and object-recognition memory deficits at six months of age, which can be prevented by doxycycline (DOX)-mediated suppression of tau expression. However, it remained unclear whether non-spatial hippocampal learning, particularly temporal associative learning, would be similarly affected. Methods: We evaluated six-month-old rTg4510 mice with or without DOX treatment. To control for potential motor confounds, we first assessed spontaneous home cage activity. We then tested hippocampus-dependent non-spatial learning using two paradigms: trace eyeblink conditioning (500-ms trace interval) and contextual fear conditioning. Results: General motor function remained intact; however, rTg4510 mice without DOX treatment exhibited increased rearing behavior. These mice demonstrated significant deficits in trace eyeblink conditioning acquisition, with particularly clear impairment on the final day of training. Contextual fear conditioning showed milder deficits. Analysis of response peak latency revealed subtle temporal processing abnormalities during early learning. Two months of DOX treatment initiated at four months of age prevented these learning deficits, confirming their association with tau overexpression. Conclusions: Our findings demonstrate that rTg4510 mice exhibit deficits in non-spatial temporal associative learning alongside previously reported spatial and object-recognition impairments. Trace eyeblink conditioning serves as a sensitive behavioral assay for detecting tau-related hippocampal dysfunction, and the prevention of learning deficits by DOX treatment highlights its potential utility as a translational biomarker for evaluating tau-targeted interventions. Full article

The identification of brain clearance failure as a precursor to a large variety of neurodegenerative diseases has shifted fluid dynamics from a secondary to a tertiary target of brain health. The identification of the glymphatic system, detailing cerebrospinal fluid entry along perivascular spaces and exit via perivenous and meningeal lymphatic pathways, provided a challenge to previous diffusion models and established aquaporin-4–dependent astroglial polarity as a governing principle of solute transport. Multiple lines of evidence now support a coupled glymphatic–venous axis, wherein vasomotion, venous outflow, and lymphatic drainage are functionally interrelated. Failure of any axis will cascade and affect the entire axis, linking venous congestion, aquaporin-4 disassembly, and meningeal lymphatic failure to protein aggregation, neuroinflammation, edema, and intracranial hypertension. Specific lines of evidence from diffusion tensor imaging along vascular spaces, clearance MRI, and multi-omic biomarkers can provide a measure of transport. Therapeutic strategies are rapidly advancing from experimental strategies to translational approval, including behavioral optimization, closed-loop sleep stimulation, vascular and lymphatic therapies, focused ultrasound, pharmacological polarity recoupling, and regenerative bioengineering. Novel computational approaches, such as digital twin dynamic modeling and adaptive trial designs, suggest that clearance measures may serve as endpoints to be approved by the FDA. This review is intended to bridge relevant mechanistic and translational reviews, focusing on impaired clearance as an exploitable systems defect rather than an incapacitating secondary effect. Improving our understanding of the glymphatic-venous axis Injury may lead to future target strategies that advance cognitive resilience, alleviate disease burden, and improve quality of life. By clarifying the glymphatic–venous axis, we provide a mechanistic link between impaired interstitial clearance and the pathological accumulation of amyloid-β, tau, and α-synuclein in neurodegenerative diseases. The repair of aquaporin-4 polarity, venous compliance, and lymphatic drainage might therefore open new avenues for the diagnosis and treatment of Alzheimer’s and Parkinson’s disease, supplying both biomarkers of disease progression and new targets for early intervention. These translational implications not only locate clearance failure as an epiphenomenon of neurodegeneration but, more importantly, as a modifiable driver of the course of neurodegeneration. Full article

Acetylcholinesterase (AChE) inhibitors are the primary target for single-molecule anti-Alzheimer’s disease (AD) therapeutics. Though AChE has historically been the focus of investigation for small-molecule inhibitors, interest in another cholinergic enzyme, butyrylcholinesterase (BChE), has grown in recent years. Attention stems from BChE’s role in β-amyloid (Aβ) protein aggregation and an increase in BChE concentration during the late stages of AD, where a decrease in AChE concentration is also observed. Currently, five FDA-approved drugs are on the market for inhibiting AChE, though no BChE-selective drugs have been approved so far. In this review, we focus on newly identified BChE selective inhibitors and present the ideas behind these discoveries. Full article

This study examines the antidiabetic potential of Rubus ulmifolius, a shrub traditionally used for medicinal and nutritional purposes. The aim was to assess the fruit extract’s inhibitory effect on α-amylase and α-glucosidase, therapeutic targets in type 2 diabetes (T2D), given their role in carbohydrate digestion. Considering the role of islet amyloid polypeptide (IAPP) aggregation in pancreatic β-cell dysfunction in T2D, the extract’s effect on inhibiting this process was also evaluated. Cytocompatibility and antioxidant effects were tested in Caco-2 cells, while caspase-1 activity was measured to evaluate anti-inflammatory potential. Phytochemical analysis of R. ulmifolius fruits revealed various phenolic compounds, with anthocyanin as the most abundant one. The cyanidin-3-O-glucoside accounted for 86% of all anthocyanins. Among flavonoids, the most represented ones were quercetin-HMG-glucoside and a kaempferol derivative, while ellagic acid glucuronide was the predominant ellagitannin. The extract showed significantly higher α-glucosidase inhibition with an IC₅₀ value of 2.8 µg/mL, 32 times more effective than acarbose, and it markedly inhibited IAPP aggregation in a dose-dependent manner. It demonstrated antioxidant activity in cellular and acellular systems, without cytotoxicity. Caspase-1 activity was also reduced in intestinal cells. These findings support R. ulmifolius fruits as a promising functional food for managing T2D and preserving pancreatic function. Full article

The islet amyloid polypeptide (IAPP) is a 37-residue peptide hormone secreted by pancreatic β-cells that is known to aggregate into amyloid fibrils. These fibrils accumulate in the pancreatic islets of individuals afflicted with type 2 diabetes and are implicated in β-cell dysfunction. Metal ions such as copper and zinc are known to modulate IAPP fibrillization, yet the role of metal-induced oxidative modifications in this process remains largely unexplored. This study examines the non-enzymatic post-translational oxidation of IAPP and its effects on aggregation using the biologically relevant Cu/O₂/ascorbate system. Mass spectrometry identified residues within the amyloidogenic region (residues 20–29) as the primary targets of oxidation. These oxidative modifications impaired the formation of cross-β-sheet amyloid fibrils and promoted the accumulation of amorphous aggregates. The H18A IAPP derivative, lacking the key metal-binding histidine, was also examined to assess the impact of sequence variation on oxidation and aggregation. Copper-mediated oxidation of H18A resulted in a broader distribution of oxidation sites and impacts fibril formation. These findings provide preliminary mechanistic insights into copper-induced oxidation and its impact on IAPP aggregation pathways. Full article

Alzheimer’s disease (AD) remains a significant public health challenge, with current treatments limited partly due to the difficulty of delivering therapeutics across the blood–brain barrier (BBB). The nose-to-brain (N-2-B) pathway offers a promising alternative to circumvent the BBB, but no drugs have yet been clinically applied via this route for AD. Mild stress is thought to activate intrinsic protective mechanisms against neurodegeneration, but traditional methods lack specificity and practicality. To address this, we propose the inhalation of mildly heated air as thermal stimulation, which utilizes the N-2-B pathway to induce mild stress and stimulate cerebral activity. This study employs thermal cycling-hyperthermia (TC-HT) in developing thermal cycling-stimulation via nasal inhalation (TCSNI), providing cyclic stimulation to maintain pathway activity while minimizing thermal injury. In C57BL/6 mice, TCSNI showed no adverse olfactory effects. In β-amyloid (Aβ)-treated mice, TCSNI significantly enhanced cognitive performance in Y-maze and novel object recognition (NOR) assessments, suggesting cognitive improvement. Mice hippocampal protein analyses indicated a reduction in Aβ accumulation, alongside increased expression of heat shock protein 70 (HSP70), insulin-degrading enzyme (IDE), and phosphorylated Akt (p-Akt). These results suggest that N-2-B-delivered TCSNI effectively modulates protein expression and enhances cognitive function, highlighting its potential for further exploration in AD treatment. Full article

Background: Early diagnosis of Alzheimer’s disease (AD) is constrained by invasive and costly tests. Aggregation of $\beta$-amyloid and the A$\beta$42/A$\beta$40 ratio in cerebrospinal fluid (CSF) and blood are key biomarkers. Fluorescent probes can report aggregate states, and artificial intelligence (AI) can extract subtle patterns from spectral and blood data. This review synthesizes how probes and AI can identify aggregates and assess the A$\beta$42/A$\beta$40 ratio in body fluids to facilitate earlier AD diagnosis. Methods: PRISMA-compliant searches were conducted in Scopus, PubMed, Web of Science, and IEEE Xplore. Results: Twenty-eight studies met inclusion criteria. Plasma A$\beta$42/A$\beta$40 was lower in PET-positive individuals by ∼7–18%, with higher performance for mass spectrometry (mean AUC ≈ 0.80) than immunoassays (AUC ≈ 0.71). CSF A$\beta$42/A$\beta$40 showed larger group differences (∼50% reductions in PET+) and stronger PET concordance, outperforming plasma. Fluorescent probes—including AN-SP and CRANAD-28—were sensitive to early aggregates and showed in vivo imaging potential, but evidence is largely preclinical or from small cohorts. AI/ML approaches frequently achieved within-study accuracies >90% (e.g., 94–100% in spectral tasks), yet external validation and head-to-head tests of ratio alone versus ratio + AI remain scarce. Conclusions: Plasma A$\beta$42/40 —particularly by mass spectrometry—currently provides the most reproducible fluid approximation to amyloid PET (mean AUC ≈ 0.80). Fluorescent probes sensitively detect oligomeric A$\beta$ species and show in vivo potential, but evidence remains largely preclinical or from small cohorts. AI/ML methods can extract additional signal from spectral and multivariate blood data, yet consistent incremental gains over optimized Aβ42/40 assays have not been demonstrated due to limited external validation and head-to-head comparisons. Full article

Alzheimer’s disease (AD) is a complex pathological process that incurs significant societal costs, yet effective treatments have not yet been developed. Novel compounds targeting β-amyloid, based on the amyloid cascade hypothesis, have failed to demonstrate clinical efficacy. Among natural products with diverse mechanisms, components contained in Astragali radix have shown anti-dementia effects in various preclinical studies, including improved cognitive function, reduced β-amyloid levels, and decreased insulin resistance. This study administered a water-extracted roasted Astragali radix (RA) to 3-month-old female 5xFAD mice for 3 months, observing changes in cognitive behavior, blood glucose, and neural signaling. RA lowered glucose levels, improved working memory, fear avoidance memory, and spatial memory, and reduced anxiety behavior in 5xFAD mice. In the hippocampus, the protein expression of BDNF and p-CREB/CREB was increased, while p-JNK/JNK was decreased. The effects of RA were similar to unroasted Astragali radix in 5xFAD mice, with some components being more abundant. Therefore, RA enhances its taste and aroma, making it suitable for long-term consumption in the form of tea, which could be effective in preventing neurodegenerative diseases such as dementia. Full article

Alzheimer’s disease (AD) has been studied extensively and is characterized by plaques deposited throughout the brain. Plaques are made of beta-amyloid (Aβ) peptides which have undergone fibrillogenesis to form insoluble Aβ fibrils (fAβ) that are neurotoxic. Receptor for Advanced Glycation End end products (RAGE), toll-like receptors (TLRs) 2 and 4, and co-receptor CD14 recognize negatively charged binding regions on fAβ to activate microglia and release proinflammatory cytokines. In this study, we used two experimentally resolved fAβ structures (type I and II) isolated from AD brain tissue to elucidate binding patterns of fAβ with RAGE, TLR2, TLR4, and CD14 and investigated whether binding was affected by fibril structure or system pH. Receptors TLR2 and RAGE formed tight complexes with both type I and II fibrils, while TLR4 showed selectivity for type I. CD14 binding was less tight and selective for type II. Binding was pH dependent for CD14, TLR4, and RAGE but not TLR2. We explored the effects of familial mutations on fibril structure to determine whether mutants of type I or II structures are feasible. Finally, we investigated whether mutations affected binding interactions of fAβ with proteins. The Arctic (Glu22Gly), Dutch (Glu22Gln), and Iowa (Asp23Asn) mutations showed similar effects on binding affinity. Italian (Glu22Lys) mutations abrogated binding, whereas type I and II fibrils with Flemish (Ala21Gly) mutations were not shown to be feasible. Results highlight the adaptability of immune receptors in recognizing damaging molecules, with fibril structure and pH being the main recognition determinants predicated on disease progression. In silico mutations showed that aggregates similar to type I and II structures were plausible for some familial mutations. Full article

Background: Apolipoprotein E (APOE) is the strongest genetic risk determinant for late-onset Alzheimer’s disease (AD). The APOE3 allele is risk-neutral, the APOE4 allele increases the risk of developing AD, and the APOE2 allele is neuroprotective. Methods: We utilized RNA sequencing of hemi-brains from a mouse model homozygous for each of these humanized APOE alleles to study gene expression profiles between mice aged 12 months of age (MO) and 18 MO, independent of β-amyloid and tau pathology. Results: More than half of the differentially expressed genes (DEGs) within each genotype were shared with at least one other APOE allele, including 1610 DEGs that were shared across the three genotypes. These DEGs represent changes driven by aging rather than APOE genotype. Aging induced DEGs and biological pathways involving metabolism, synaptic function, and protein synthesis, among others. Alterations in these pathways were also identified by DEGs unique to APOE4, suggesting that the APOE4 allele drives the aging phenotype. In contrast, fewer pathways were identified from DEGs unique to APOE2 or APOE3. Conclusions: Transcriptomic results suggest that the most significant impact on brain-level expression changes in humanized APOE mice is aging and that APOE4 exacerbates this process. These in vivo findings within an established model system are consistent with brain aging being the greatest risk factor for AD and suggest that APOE4 expression promotes an aging phenotype in the brain that interacts with, and contributes to, aging-driven AD risk. Results reinforce the impact age and APOE allele contribute to AD and age-related neurodegeneration, and foster greater mechanistic understanding as well as inform therapeutic intervention. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder involving free radical overload, neuroinflammation, and a deranged cell stress response. In particular, the modulation of the heme oxygenase/biliverdin reductase (HO/BVR) system, a key component of the brain stress response, is currently regarded as a promising therapeutic approach for AD. Cellular senescence, defined as a process of cell cycle arrest due to oxidative stress, DNA damage, mitochondrial dysfunction, and oncogene activation, has been identified as a pivotal factor in the development of AD. A mounting body of research has demonstrated that the accumulation of senescent cells in the brain can lead to a variety of neurotoxic effects, including synaptic dysfunction, the destruction of the blood–brain barrier, and impaired remyelination. Finally, the release of proinflammatory molecules by senescent cells further exacerbates neurodegeneration. A considerable number of xenobiotics, with well-documented neuroprotective effects through the activation of the HO/BVR system, have been shown to modulate pathways involved in cellular senescence outside the brain. Unfortunately, a direct link between HO/BVR and cellular senescence in AD is yet to be established. This compelling evidence should motivate basic and clinical researchers to address such a significant gap in knowledge and conduct novel studies in this field. Full article

Background: The pathogenesis of Alzheimer’s disease (AD) is complex, and effective treatments remain elusive. Growing evidence suggests that dietary factors may play a significant role in preventing or alleviating AD. Bergapten (BG), a natural compound with anti-inflammatory properties, has been studied; however, its specific role in neuroinflammation and AD pathogenesis remains unclear. Methods: Through public databases and bioinformatics tools, the possible molecular mechanisms of BG’s effects on AD were analyzed. Six-month-old 5×FAD mice underwent intragastric administration of BG for 30 consecutive days. Learning and memory abilities were assessed using the novel object recognition (NOR) test and the Morris water maze (MWM) test. Immunofluorescence staining, Western blot and q-PCR was conducted to assess the underlying mechanisms. In vitro experiments used Aβ-stimulated BV2 microglial cells for BG intervention. Results: Bioinformatics analysis revealed the MAPK signaling pathway as the top-ranked pathway. Molecular docking studies further demonstrated strong binding interactions between BG and key proteins within the MAPK pathway. In behavioral studies, NOR test and MWM test demonstrated that BG treatment improved learning and memory abilities in 5×FAD mice. Additionally, BG treatment significantly reduced Aβ deposition, pro-inflammatory cytokine levels, and inhibited excessive microglial activation in these mice. Consistent with in vivo findings, BG effectively decreased pro-inflammatory cytokines in Aβ-stimulated BV2 microglial cells. Mechanistic studies revealed that BG attenuates neuroinflammatory responses by inhibiting the MAPK signaling pathway both in vivo and in vitro. Conclusions: Our findings suggest that BG mitigates AD pathological features by suppressing MAPK-mediated neuroinflammation and represents a promising natural small molecule for the prevention and treatment of AD. Full article