Search Results (516)

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β aggregation, tau hyperphosphorylation, oxidative stress, and mitochondrial dysfunction. Emerging evidence indicates that the gut microbiota plays a critical role in modulating neuroinflammatory, and metabolic pathways involved in AD pathogenesis through the microbiota-gut-brain axis. Objective: This systematic review aims to comprehensively evaluate the role of the microbiota-gut-brain axis in Alzheimer’s disease, with a particular focus on its mechanistic links to oxidative stress, mitochondrial dysfunction, and amyloid pathology, as well as its therapeutic potential. Methodology: A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science databases, focusing on studies evaluating gut microbiota composition, metabolomic changes, oxidative stress markers, mitochondrial activity, and therapeutic interventions in AD models and patients. Results: Altered gut microbial composition in AD is associated with increased pro-inflammatory taxa (Escherichia-Shigella, Bacteroides) and depletion of short-chain fatty acid (SCFA) producing bacteria (Faecalibacterium, Roseburia). Dysbiosis contributes to systemic inflammation, disrupted intestinal permeability, and microglial activation, leading to oxidative damage and mitochondrial impairment in neurons. Preclinical and clinical studies indicate that probiotics, prebiotics, and fecal microbiota transplantation can restore redox balance, reduce neuroinflammation, and improve cognitive outcomes. Multi-omics and AI-based models are emerging as tools for identifying microbiome-derived biomarkers for early AD detection. Conclusion: The gut microbiota-mitochondria-oxidative stress axis represents a promising therapeutic target in Alzheimer’s disease. Future research should focus on longitudinal human studies, standardized microbial profiling, and personalized microbiome-based interventions to translate these mechanistic insights into clinical benefit. Full article

Recent studies support the concept of a bidirectional lung–brain axis. While neural, immune, and microbial pathways are increasingly recognized in lung-to-brain communication, the role of matrikines—bioactive peptides generated by extracellular matrix (ECM) proteolysis during remodeling—in this inter-organ communication remains underexplored. This review highlights matrikines originating from the lung, particularly the collagen-derived tripeptide Pro-Gly-Pro (PGP) and the elastin-derived hexapeptide Val-Gly-Val-Ala-Pro-Gly (VGVAPG), as potential mediators linking pulmonary pathology with neurological outcomes. The lung is rich in ECM proteins, and inflammatory conditions such as chronic obstructive pulmonary disease (COPD) and emphysema trigger proteolytic activity by matrix metalloproteinases (MMPs) and neutrophil elastase, releasing matrikines into circulation. Under conditions of blood–brain barrier (BBB) dysfunction, they may access the central nervous system (CNS), where they influence neurons, microglia, and astrocytes, modulating neuroinflammation, autophagy, and synaptic integrity. While PGP can exhibit context-dependent neuroprotective effects, its acetylated form and VGVAPG are associated with neurotoxicity, Tau hyperphosphorylation, and microglial activation. Additional matrikines, including Gly-His-Lys (GHK) and endorepellin, may further modulate CNS homeostasis. Collectively, these findings support lung-derived matrikines as circulating mediators of lung-to-brain signaling, providing a novel mechanistic framework linking chronic pulmonary inflammation to neuropathologies, such as stroke and neurodegenerative disorders, and highlighting potential targets for therapeutic intervention. Full article

Diabetes Mellitus is a chronic metabolic disorder characterized by impaired insulin production and/or action, leading to persistent hyperglycemia and insulin resistance. It has been associated with several comorbidities, including cognitive dysfunction, affecting functions such as attention, memory, and processing speed. Mounting evidence indicates a complex relationship between type 2 Diabetes Mellitus (DM2) and neurodegenerative disorders such as mild cognitive impairment and Alzheimer’s disease (AD). Beyond the conventional hallmarks of each pathology, patients with DM2 face an increased risk of neuronal degeneration, while AD is characterized by a marked reduction in insulin receptor density. Although aging, neuroinflammation, and vascular dysfunction have been recognized as key risk factors in AD, the precise molecular mechanisms driving AD pathogenesis remain incompletely understood. Various studies have been conducted to identify reliable biomarkers that elucidate the connection between DM2 and AD, including insulin dysregulation, neuroinflammation, amyloid-β aggregation, and tau hyperphosphorylation. Investigation of these biomarkers is still ongoing, and they may serve not only as diagnostic tools but also as therapeutic targets. Here, we review the current evidence supporting a convergent biological framework between DM2 and AD. Clarifying these shared pathways may improve early detection and guide the development of targeted therapeutic strategies aimed at reducing neurodegeneration in metabolically vulnerable populations. Full article

Alzheimer’s (AD) and Parkinson’s disease (PD) are prominent neurodegenerative disorders characterized by early synaptic loss, which correlates more closely with clinical symptoms than neuronal death. This synaptic impairment is primarily driven by disruptions in synaptic vesicle (SV) trafficking, a critical process for maintaining synaptic integrity through a tightly regulated cycle involving clustering, docking-priming, Ca²⁺-triggered fusion, and endocytosis. In AD, amyloid-β (Aβ) oligomers interfere with SNARE-mediated fusion and endocytosis, while hyperphosphorylated tau obstructs vesicle mobility and docking, resulting in cumulative toxicity that aggravates SV defects. Conversely, in PD, α-synuclein (α-syn) aggregation alters vesicle clustering, membrane fusion, and recycling, and these effects are further influenced by Leucine-rich repeat kinase 2 (LRRK2)-Rab-related trafficking defects and the selective vulnerability of dopaminergic terminals. Different from previous reviews that address synaptic dysfunction in a broader manner, the present review is specifically organized around the SV trafficking cycle and compares both shared presynaptic endpoints and disease-specific upstream mechanisms in AD and PD. In addition, recent mechanism-oriented therapeutic strategies are summarized. This vesicle-cycle-centered perspective may provide a clearer framework for understanding presynaptic pathology and for guiding the development of earlier and more targeted interventions. Full article

Type 2 Diabetes (T2D) is characterized by the toxic aggregation of human islet amyloid polypeptide (hIAPP or amylin) within pancreatic β-cells. IAPP is also a neuropancreatic hormone that plays a significant role in Alzheimer’s disease (AD) by co-depositing with amyloid-beta (Aβ) and Tau, supporting the Type 3 Diabetes (T3D) hypothesis. Soluble IAPP accelerates Aβ aggregation through cross-seeding and causes neurotoxicity by impairing the blood–brain barrier and activating neuroinflammation. Melatonin inhibits these processes by disrupting hydrophobic interactions in both hIAPP and Aβ, preventing the formation of toxic β-sheet structures. Furthermore, melatonin promotes amyloid clearance via the glymphatic and lymphatic systems, protects neurons from oxidative damage, and reduces Tau hyperphosphorylation. This suggests that melatonin serves as a promising multitarget therapeutic agent for both metabolic and neurodegenerative disorders by modulating structural protein transformations. Full article

Gelatin hydrolysate (GH), a bioactive compound derived from collagen, has demonstrated potential therapeutic benefits in various medical conditions. However, its effects on chronic cerebral hypoperfusion-induced vascular dementia remain underexplored. This study aimed to investigate the anti-oxidative stress effects of GH in alleviating brain damage and cognitive impairment in CCH-induced rats. Male Wistar rats underwent bilateral common carotid artery occlusion to induce CCH and were randomly divided into five groups: (1) sham, (2) 2-vessel occlusion (2VO), (3) 2VO + 250 mg/kg GH, (4) 2VO + 500 mg/kg GH, and (5) 2VO + piracetam. Treatments were administered for 35 days of post-operation. GH treatment significantly mitigated oxidative stress, as evidenced by reduced levels of reactive oxygen species (ROS), nitric oxide (NO), and the expression of 4-hydroxynonenal (4-HNE) and NADPH oxidase 4 (NOX4). Furthermore, GH exhibited antioxidant activity by upregulating superoxide dismutase (SOD) levels via nuclear factor E2-related factor 2 (Nrf-2) activation. This, in turn, reduced neuronal apoptosis by decreasing Bax and cleaved-caspase 3 levels and increasing Bcl-2 expression. Additionally, GH treatment ameliorated Tau protein hyperphosphorylation and improved synaptic function. Overall, GH exerted neuroprotective effects against oxidative stress-related neuronal damage and enhanced neuroplasticity, learning, and memory in rats with CCH-induced cognitive impairment. Full article

Alzheimer’s disease (AD) is a rapidly escalating global health crisis with limited effective treatments. Emerging research underscores the pivotal role of the microbiota–gut–brain axis in AD pathogenesis, prompting the exploration into gut microbiota-targeted interventions. This narrative review aimed to comprehensively synthesize the latest epidemiological, experimental, and clinical evidence regarding the effects and mechanisms of probiotics, prebiotics, synbiotics, and postbiotics (PPSPs) in AD prevention and management. We conducted a narrative review of relevant literature from the Web of Science and PubMed databases. The search focused on articles published within the last 5 years using keywords such as “Alzheimer’s disease”, “AD”, “gut-brain axis”, “gut microbiota”, “probiotics”, “prebiotics”, “synbiotics”, and “postbiotics”. The findings suggest that PPSPs mitigate AD pathology and improve cognitive performance by modulating gut microbiota, strengthening intestinal barrier integrity, decreasing amyloid-beta (Aβ) deposition and tau hyperphosphorylation, reducing neuroinflammation and oxidative stress, regulating neurotransmitter metabolism, and promoting synaptic plasticity. Some studies also report varied outcomes, attributable to factors like strain specificity, dosage, intervention duration, patient heterogeneity, and methodological differences. In conclusion, targeting the microbiota–gut–brain axis with PPSPs offers a promising, mechanism-based strategy for AD, though further research is essential to optimize specific interventions for clinical application. Full article

Alzheimer’s disease (AD) is a catastrophic neurodegenerative disorder marked by progressive decline of cognitive function, memory loss, and neuronal death. Its pathology is characterized by the formation of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles from tau hyperphosphorylation. Despite extensive research, current treatments are limited to symptomatic relief and are associated with significant side effects. This accentuates the critical need for alternative therapeutic strategies with potent neuroprotective effects and minimal toxicity. This study investigates the neuroprotective potential of glycyrrhizic acid, as the precise molecular mechanisms by which it might improve AD pathology remain poorly understood. Using an Aβ₄₂-induced IMR-32 cell model of AD, our research revealed that Aβ₄₂ treatment caused significant protein alterations associated with AD pathology, mitochondrial dysfunction, cell cycle re-entry, and synaptic activity. Co-treatment with glycyrrhizic acid not only restored these protein levels, but also mitigated the hyperactivation of several key signaling pathways and rescued neurons from apoptosis. These findings suggest that glycyrrhizic acid exerts neuroprotective effects by preventing mitochondrial dysfunction and apoptosis via modulation of critical signaling pathways. This study provides strong evidence for glycyrrhizic acid’s neuroprotective properties in AD, paving the way for further research into its potential as a promising therapeutic agent for Alzheimer’s disease. Full article

Alzheimer’s disease (AD) is an aging-associated neurodegenerative disorder in which dysregulated neuroinflammation drives disease progression. Although long noncoding RNAs (lncRNAs) are increasingly implicated in AD, their mechanistic roles remain poorly defined. Here, we identified a novel lncRNA termed LIMASI (LncRNA Inflammation and Mucous associated, Antisense to ICAM1), that is linked with AD-associated neuroinflammation. LIMASI expression is significantly elevated in postmortem AD brain tissues and in a 3xTg-AD mouse model by qPCR and RNA fluorescence in situ hybridization, and its upregulation is correlated with increased β-amyloid plaque burden, tau hyperphosphorylation, and heightened neuroinflammatory activation. Cell type-specific analyses demonstrated inflammation-inducible LIMASI expression in astrocytes and microglia. In an in vitro model of AD-associated neuroinflammation, viral mimetic poly(I:C) challenge of amyloid precursor protein (APP)-overexpressing neuroblastoma cells elicited coordinated induction of LIMASI and key inflammatory mediators. Mechanistically, we observed elevated levels of inflammatory microRNAs (miR-155-5p and miR-150-5p) in AD brain tissues, and computational modeling predicted energetically favorable interactions between these miRNAs and LIMASI. These findings support a competing endogenous RNA (ceRNA) model in which LIMASI sequesters pro-inflammatory miRNAs to modulate neuroinflammatory gene networks. Together, our data identify LIMASI as a putative ceRNA strongly associated with AD-related neuroinflammation and suggest that targeting LIMASI may represent a novel strategy to attenuate neuroinflammatory signaling and potentially slow AD-associated neurodegeneration. Full article

Most dementias are preceded by mild cognitive impairment (MCI), a transitional clinical stage characterized by cognitive decline that does not yet significantly interfere with activities of daily living. Obesity and diabetes are among the major risk factors for MCI and are strongly associated with unhealthy lifestyle patterns. The growing global prevalence of obesity has intensified the need for effective dietary strategies that promote both weight control and neuroprotection. Red fruits, which are rich in bioactive compounds such as anthocyanins, have demonstrated potential roles in modulating metabolic pathways and cognitive function. This systematic review aimed to identify and synthesize evidence from human studies published over the past two decades that examined the effects of red fruit consumption on obesity-related mechanisms and cognitive outcomes, as well as its influence on key neurodegenerative biomarkers, including TAU protein, β-amyloid, and neurofilament light chain. A systematic search was conducted in major scientific databases to identify human clinical trials evaluating the metabolic and neuroprotective effects of berry-derived compounds. Eligible studies were screened for outcomes related to cognitive performance, obesity-related parameters, and relevant molecular biomarkers. The included studies reported modest improvements in cognitive domains, with the most consistent effects observed in memory-related outcomes. Berry-derived bioactive compounds demonstrated potential in attenuating TAU protein hyperphosphorylation and reducing β-amyloid accumulation; however, the available evidence remains limited and requires further confirmation. Human clinical studies remain scarce, and although some trials reported favorable metabolic effects, these findings are still inconclusive. Reported outcomes included improvements in insulin sensitivity, regulation of leptin levels, and modulation of the gut–brain axis, which may collectively contribute to a reduced risk of obesity. Based on the studies evaluated in this review, there remains a limited number of human clinical trials that robustly support the neuroprotective and complementary metabolic effects of berry-derived bioactive compounds. Nevertheless, the available evidence suggests that dietary strategies incorporating wild fruits rich in polyphenols may represent a promising complementary approach for the prevention of mild cognitive impairment (MCI) and obesity, with potential implications for reducing the risk of dementia progression. Full article

Alzheimer’s disease is the most common cause of dementia and one of the greatest challenges of current medicine. Its pathophysiology is complex, involving β-amyloid deposition, tau hyperphosphorylation, chronic neuroinflammation, and progressive neuronal loss. Despite the introduction of novel therapies, treatment efficacy remains limited, prompting the search for alternative therapeutic targets. One promising area of research focuses on matrix metalloproteinases-proteolytic enzymes involved in tissue remodeling, synaptic plasticity, and inflammatory responses. In the context of AD, MMPs may exert both protective effects, through amyloid degradation, and detrimental effects such as blood–brain barrier disruption and amplification of neuroinflammatory damage. Understanding the dual and context-dependent roles of MMPs may help explain past translational failures and enable the development of more selective, stage-dependent therapeutic strategies. This article is a narrative review summarizing current evidence on the roles of MMPs in AD, with a particular focus on their therapeutic modulation and potential implications for future clinical research. Insights into MMP biology may ultimately guide the design of interventions with improved efficacy and safety for patients with AD. Full article

This study sought to evaluate the neuroprotective effects of YGD in an oxidative stress-induced Alzheimer’s disease (AD)-like cellular model and to elucidate the underlying molecular pathways, with a focus on tau phosphorylation, Aβ accumulation, and antioxidant defense mechanisms. Rat primary hippocampal neurons were exposed to hydrogen peroxide to induce oxidative stress. The effects of YGD on neuronal viability, neurite outgrowth, and synaptic integrity were assessed using the immunodetection of microtubule-associated protein 2 (MAP2), postsynaptic density protein 95 (PSD-95), and synapsin-1. Levels of phosphorylated tau and Aβ were quantified, and the involvement of extracellular signal-regulated kinase (ERK), glycogen synthase kinase 3β (GSK3β), and nuclear factor-erythroid 2-related factor-2 (Nrf2) pathways was examined. Additionally, in silico molecular docking studies targeting the ATP-binding site of GSK3β were conducted to screen major phytochemicals from the ten medicinal herbs constituting YGD. YGD markedly enhanced neuronal viability under oxidative stress, promoted neurite extension, and increased synaptic marker expression (MAP2, PSD-95, and synapsin-1). Treatment reduced phosphorylated tau by suppressing ERK and GSK3β activation and significantly decreased Aβ accumulation. YGD also upregulated antioxidant defenses via the activation of the Nrf2 pathway. Docking simulations identified oleanolic acid (from Cornus officinalis) as the most potent GSK3β binder (−9.86 ± 0.40 kcal/mol), forming stable interactions with ARG96, ASN95, and GLU97. Additional compounds, including alisol C, drypemolundein B, and friedelin, demonstrated favorable binding energies and engaged key ATP-binding site residues. YGD confers neuroprotection through the integrated modulation of tau phosphorylation, Aβ pathology, and oxidative stress, partly via the multi-target engagement of GSK3β by its constituent phytochemicals. These findings support that YGD attenuates oxidative stress-induced AD-like cellular alterations. Full article

Alzheimer’s disease (AD) is marked by amyloid plaques, hyperphosphorylated TAU proteins, and neuroinflammation. The APP/PS1 mouse model is widely used to study AD pathogenesis. In this study, we investigated the expression of chemokines and their receptors, which may play a role in AD’s pathological mechanisms, using brain cortex tissue from female APP/PS1 mice aged 20–21 months. We analyzed several chemokine receptors (CCR1, CCR2, CCR3, CCR4, CCR6, CCR7, CCR9, and CCR10) by Western blot and focused on CCR6, CCR7, and CCR10 using RT-PCR. Additionally, we quantified the levels of chemokines (CCL6, CCL8, CCL19, CCL20, CCL24, and CCL27) by RT-PCR. Our results showed a significant decrease in CCL8 and CCL19, along with their respective receptors, in the APP/PS1 mice compared to controls. On the other hand, we observed a notable increase in CCL6, CCL24, CCL20, CCL27, and their receptors. Chemokines like CCL8 and CCL20, involved in inflammatory responses, may reveal how neuroinflammation contributes to AD. CCL19 and CCL27 are linked to immune cell trafficking, which may help explain immune cell interactions with amyloid plaques and TAU tangles in the CNS. Overall, the altered expression of chemokines such as CCL24 could serve as biomarkers for early AD detection and monitoring disease progression. These findings suggest potential therapeutic targets to modulate immune responses and reduce neuroinflammation in AD. Full article

Alzheimer’s disease (AD) is characterized by progressive cognitive decline, with amyloid beta oligomers (AβOs) emerging as the most neurotoxic species and acting as early triggers of cellular alterations. Before the appearance of other protein aggregates, AβOs disrupt the dynamics and stability of the neuronal cytoskeleton, a structure essential for maintaining neuronal morphology, axonal transport, and synaptic plasticity. Experimental evidence demonstrates that AβOs promote microtubule disassembly, Tau hyperphosphorylation, reduced kinesin levels, impaired axonal transport, and alterations in actin dynamics through the LIMK–cofilin signaling pathway. In addition, increased levels of neurofilament light chain have been identified as an early biomarker of axonal damage. Notably, these cytoskeletal disturbances arise in the absence of extensive neuronal death, underscoring the cytoskeleton as a critical early target in AD pathogenesis. In this review, we analyze cytoskeletal alterations induced by AβOs in neurons and discuss how these changes may contribute to disrupted neuronal communication, a defining early hallmark of AD pathology. Full article

Circadian disruption (CD) has emerged as a critical factor compromising human health in contemporary society. Increasing evidence suggests that disturbances in circadian rhythms are involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease (AD). The hyperphosphorylation of tau and the deposition of amyloid-β (Aβ) are recognized as major pathological hallmarks of AD. In this study, we aimed to explore the impact of long-term CD on AD-like pathological changes and to explore the underlying molecular mechanisms using a mouse model. To mimic the CD experienced by shift workers, mice were subjected to lighting conditions involving repeated reversals of the light–dark cycle. In this study, qPCR was to employed detect the expression profile of clock genes in the hippocampus. Subsequently, Western blotting and immunohistochemical analyses were used to evaluate AD-like pathological changes in the hippocampus following CD. For elucidating the underlying mechanisms, we assessed circadian expression patterns of major neurotransmitters, activation of microglia and astrocytes, and alterations of tight junction proteins within the hippocampus. Our findings demonstrated that light–dark cycle disruption triggered CD in mice, and then CD led to increased expression of Aβ protein and tau hyperphosphorylation. CD significantly disrupted the circadian expression profiles of hippocampal clock genes and major neurotransmitters, induced microglial and astrocytic activation, and decreased the expression of the tight junction proteins zonula occludens-1 and occludin in the hippocampus. These results suggest that changes in the light–dark cycles induced abnormal expression of hippocampal clock genes involved in circadian rhythm regulation, suggesting that the body is in a state of endogenous CD. CD induces AD-like pathological changes in mice, potentially mediated by dysregulated circadian oscillations of clock genes, neuroinflammation, loss of key blood–brain barrier proteins, and disturbed neurotransmitter expression in the hippocampus. Collectively, this study underscores the importance of circadian stability for brain health, and highlights the necessity for deeper exploration into the connection between AD and CD. Full article