Search Results (1,635)

Mitochondrial dysfunction is a relevant hallmark of Alzheimer’s disease (AD), contributing to the impaired metabolic homeostasis involved in neuronal loss and cognitive decline. In this study, we target the metabolic dysfunction occurring in AD through a novel pharmacological approach involving the modulation of glutamate dehydrogenase (GDH), which converts glutamate to α-ketoglutarate and supports the tricarboxylic acid (TCA) cycle. In our experimental models (i.e., differentiated SH-SY5Y cells and primary rat cortical neurons exposed to glyceraldehyde and amyloid-beta peptide 1-42, respectively), the allosteric GDH activator 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) increased mitochondrial ATP production, improved cellular bioenergetics, and reduced oxidative stress, ultimately promoting neuronal survival. Ionic dysfunctions in AD are linked to disrupted calcium homeostasis and organelle storing properties. In this context, GDH activation potentiated mitochondrial and endoplasmic reticulum calcium buffering capacity by enhancing store-operated calcium entry. Oxidative stress, largely driven by mitochondrial ROS overproduction, represents another major contributor to AD pathology. In our AD models BCH-mediated GDH activation reduced ROS formation and restored mitochondrial membrane potential (ΔΨ_m). Importantly, these metabolic and ionic improvements were associated with decreased accumulation of amyloid-β (Aβ_1-42) and phosphorylated tau (pTau), two key AD biomarkers. Overall, modulation of the GDH/TCA pathway represents a promising approach for restoring metabolic dysfunctions and counteracting oxidative stress and ionic dysregulation and therefore AD neurodegeneration. Full article

Alzheimer’s disease (AD) research has primarily focused on amyloid beta (Aβ) and tau protein; however, drug development targeting these two proteins has been disappointing. Therefore, there is an urgent need to explore the novel pathogenic mechanisms underlying AD. Recently, we found that expression of the K670N/M671L-mutated amyloid precursor protein (APP) in 293T cells significantly reduced membrane ferroportin (FPN) levels. Furthermore, 2-month-old APP/PS1 mice exhibited a marked decrease in membrane FPN levels, while total FPN expression and Aβ levels remained unchanged. Further studies revealed that features of ferroptosis were present in the brains of 2-month-old APP/PS1 mice, and that treatment with ferroptosis inhibitors or iron chelation significantly alleviated early pathological changes and cognitive impairment in these animals. In addition, supplementation with an APP–FPN binding peptide during the early phase ameliorated AD-related pathologies, including Aβ deposition, neuroinflammation, oxidative stress, and synapse-associated protein deficits, in APP/PS1 mice. Collectively, our findings suggest that APP mutations may contribute to early brain pathological changes and subsequent memory impairment in AD by downregulating membrane trafficking of FPN and inducing ferroptosis, thereby providing new molecular targets for drug development. Full article

Background/Objectives: Alzheimer’s disease (AD) is characterized by amyloid-beta accumulation and neuroinflammation, yet the molecular target of Ginsenoside Rg1 remains elusive. This study aimed to elucidate the neuroprotective mechanism of Ginsenoside Rg1, specifically investigating its interaction with C-C motif chemokine receptor 3 (CCR3). Methods: We utilized 5xFAD transgenic mice and CCR3-overexpressing BV2 microglial cells. Behavioral assessments, enzyme-linked immunosorbent assays, quantitative real-time polymerase chain reaction, molecular docking, and surface plasmon resonance were employed to evaluate cognitive function and molecular pathways. Results: Ginsenoside Rg1 treatment significantly ameliorated spatial learning and memory deficits. Quantitatively, Rg1 reduced cortical amyloid-beta 1–40 levels (p < 0.05) and bound directly to CCR3 with a dissociation constant of 3.599 × 10⁻⁵ mol/L. This inhibition suppressed neuroinflammation and restored neurotrophic factors, including Brain-derived neurotrophic factor. Conclusions: CCR3 is a novel pharmacological target for Ginsenoside Rg1, providing a precise molecular basis for its neuroprotective effects. Future research should focus on clarifying the pharmacokinetic profile and brain bioavailability of Ginsenoside Rg1 to facilitate clinical translation. Full article

Alzheimer’s disease (AD) develops as a progressive dementia condition through the step-by-step breakdown of nerve cells. Neurodegeneration in this context primarily results from metal ions, including copper, iron, zinc, and aluminum, building up in the system. The aggregation of amyloid-beta (Aβ) peptides and oxidative stress generation stem from metal ion involvement acting as defining characteristics of Alzheimer’s disease pathology. We developed a comprehensive mathematical model based on 24 coupled ordinary differential equations (ODEs) to represent the interactions between metal ions, Aβ peptides, reactive oxygen species (ROS), antioxidant defenses, and tau protein phosphorylation. The mathematical model monitors how metal ion concentrations change over time and examines their competitive binding effects, which trigger a series of reactions, resulting in oxidative stress and subsequent tau protein damage. The model uses analytical and numerical mathematical methods to expose nonlinear behaviors and threshold effects while offering mechanistic insights into the course of disease development. This model functions as a quantitative framework for assessing how therapeutic interventions that target metal dyshomeostasis and oxidative stress can potentially affect outcomes. Full article

Advanced Glycation End Products (AGEs) are reactive compounds formed through the non-enzymatic glycation of proteins, lipids, or nucleic acids due to exposure to reducing sugars. They accumulate through endogenous metabolic dysregulation and exogenous dietary intake, particularly high-fat and high-sugar foods prepared at high temperatures. The interaction between AGEs and their receptor, RAGE (receptor for Advanced Glycation End Products), has been implicated in a range of pathological conditions, including diabetes and metabolic syndrome. However, the impact of AGEs accumulation on neurodevelopment remains poorly understood. In this study, we investigated the effects of AGEs on human-induced pluripotent stem cell (iPSC)-derived cerebral organoids comprising neurons, astrocytes, and microglia. Our findings reveal that AGEs induce RAGE expression, leading to microglial activation, increased deposition of amyloid-beta (Aβ) aggregates, and impaired neurodevelopment. Additionally, elevated levels of AGE-modified proteins, along with altered microglial polarization, were observed in cerebral organoids modeling Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism–Dementia Complex (ALS-PDC). These findings demonstrate AGEs as active drivers of neurodevelopmental disruption and establish a mechanistic link between metabolic stress and increased susceptibility to neurodegenerative disease. Full article

Background/Objectives: Beta amyloid (Aβ) aggregates play a central role in the pathophysiology of Alzheimer’s disease (AD), and their detection and modulation remain major challenges in developing effective therapeutic and diagnostic strategies. Previously, gold nanoparticles with plasmonic and optical properties in the near-infrared (NIR) region and photothermal capabilities have been designed for detecting and disaggregating Aβ aggregates. However, these systems often face limitations related to biodegradability, long-term accumulation, and safety. In this work, a degradable NIR-responsive nanosystem based on small gold nanoparticles (sAuNPs), potentially excretable due to their small size, encapsulated within bovine serum albumin (BSA) and functionalized with the all-D peptide D3, was developed to inhibit Aβ aggregation. Methods: sAuNPs (~5–6 nm), functionalized with HS-PEG-NH₂, were encapsulated into BSA nanoparticles using a desolvation method and subsequently conjugated to D3, resulting in the nanosystem f-sAuNPs-BSANPs-D3. The nanosystem was characterized by UV–Vis–NIR spectroscopy, dynamic light scattering, zeta potential analysis, electron microscopy, and nanoparticle tracking analysis. The effects of the nanosystem on Aβ_1–42 aggregation were evaluated using a thioflavin T assay and electron microscopy. Additionally, the effects of f-sAuNPs-BSANPs-D3 on cell viability and its stability against trypsin digestion were assessed. Results: The nanosystem exhibited a measurable photothermal response under NIR irradiation and significantly reduced fibril formation. It did not affect the viability of SH-SY5Y neuronal cells at the tested concentrations. Trypsin incubation experiments demonstrated that the nanosystem remained stable at low enzyme concentrations mimicking plasma conditions, whereas higher enzyme concentrations induced degradation of the albumin matrix and subsequent disaggregation of sAuNPs. Conclusions: Overall, this study presents a degradable, albumin-based sAuNP nanosystem with NIR-responsive properties and potential for nanomedicine applications to inhibit Aβ aggregation in AD. Full article

Alzheimer’s disease (AD) is primarily recognized for progressive cognitive decline driven by beta-amyloid accumulation and tau pathology. However, many individuals with AD also experience chronic pain and depressive symptoms, which significantly impair daily functioning and quality of life and increase caregiver burden. These non-cognitive features are frequently underrecognized, despite evidence suggesting they share overlapping biological pathways with neurodegeneration. Emerging data highlight the role of neuroinflammation, oxidative stress, hypothalamic–pituitary–adrenal axis dysregulation, and endocannabinoid system alterations in linking AD pathology to disturbances in pain processing and mood regulation. Persistent microglial activation, cytokine imbalance, redox disruption, and chronic stress signaling may simultaneously promote neuronal vulnerability while shaping affective and nociceptive responses. This review synthesizes current preclinical and clinical evidence on the interplay between pain, depression, and AD, emphasizing their shared pathophysiological mechanisms and clinical relevance. Recognizing these symptoms as integral components of disease progression, rather than isolated comorbidities, can inform the development of integrated, multidimensional therapeutic strategies in AD care. Full article

Alzheimer’s disease is a complex neurodegenerative condition characterized by progressive cognitive decline, neuroinflammation, metabolic dysregulation, and abnormal protein deposition. While genetic factors and amyloid-beta-focused hypotheses have been extensively investigated, they fail to fully account for the prolonged prodromal phase or the early susceptibility of olfactory and limbic regions. Emerging evidence suggests chronic peripheral and mucosal infections may influence disease risk; however, mechanisms by which microbial activity outside the central nervous system contributes to persistent neuropathology remain poorly understood. This review explores the emerging concept that bacterial outer membrane vesicles act as mobile, lipid-rich vectors linking peripheral microbial reservoirs to neuroimmune and metabolic dysfunction in the aging brain. We discuss evidence suggesting vesicles originating from oral, olfactory, and upper airway niches can access the central nervous system via vascular routes and direct neural pathways, including olfactory and trigeminal nerves, where they influence glial and endothelial cell function. We also propose the Accumulative Vesicle Load Hypothesis, which describes how cumulative lifetime exposure to bacterial vesicles shapes disease onset, anatomical vulnerability, and progression, and incorporates components of other hypotheses proposed for Alzheimer’s disease. This offers a system-level perspective for early diagnosis and upstream therapeutic strategies, including minimally invasive vesicle profiling in nasal fluid, saliva, blood, and cerebrospinal fluid. This work is a conceptual review that summarizes current evidence in a hierarchically organized manner and proposes a testable model; it does not assert causality where direct human evidence is currently limited. Full article

Alzheimer’s disease is a devastating progressive neurodegenerative disorder characterized by extracellular amyloid-beta plaques and intracellular tau tangles. Despite recent advancements in amyloid-beta-targeting immunotherapies, achieving safe and definitive disease control remains a profound clinical challenge. The CRISPR/Cas9 system has emerged as a powerful technology for precision neurogenetics, offering significant potential to address the fundamental questions behind Alzheimer’s disease. This comprehensive review delineates the trajectory of CRISPR applications in Alzheimer’s disease research and therapeutics. First, we explore the integration of CRISPR in engineering high-fidelity in vitro models, such as isogenic induced pluripotent stem cells and three-dimensional cerebral organoids, alongside advanced in vivo mammalian models. Second, we examine how these platforms facilitate unbiased high-throughput genetic screening to uncover molecular underpinnings regulating tau, lipid metabolism, and neuroinflammation. Third, we critically evaluate precision editing strategies targeting core risk genes (APP, MAPT, APOE, and TREM2), explicitly highlighting the severe physiopathological trade-offs between therapeutic efficacy and loss-of-function toxicity. Finally, we address the ultimate translational bottlenecks impeding clinical application. By dissecting the packaging limits of adeno-associated viral vectors and the physical barricade of the blood–brain barrier, we underscore the necessity of transitioning toward next-generation base editors and non-viral lipid nanoparticles to realize safe and efficacious in vivo clinical gene therapies against Alzheimer’s disease. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder first described more than one century ago. Over this time, many features of the disease have been discovered and, consequently, many different approaches in the diagnosis and treatment of AD have been developed. A major assumption has guided research on AD in the past: this fatal form of cognitive decline is believed to have a pathogenic basis in the deposition of amyloid beta (Aβ) aggregates throughout the brain. Consequently, a main goal of AD therapy is to reduce Aβ load, and several monoclonal antibodies targeting amyloid are among the most recent approaches to AD treatment. However, the effectiveness of these drugs is limited, as they cannot block the progression of the disease; they only slow it down in certain conditions. Many other causative factors are known to promote the development of the disease, with immune system involvement being the most investigated. Indeed, it has been well documented that the microglial response enhances the deposition of other altered proteins, such as Tau, and induces a neurotoxic microenvironment that promotes neuronal loss. In this scenario, the interaction between microglia and astrocytes is known to accelerate pathogenic processes, and a possible role for peripheral T lymphocytes in AD pathology has also been described. An interesting hypothesis is that immune cells driving chronic inflammation might worsen AD progression and, therefore, could represent a target for treatment strategies in this disease. Thus, this review article aims to summarise the role of brain and peripheral immune molecules and cells in AD. Also, immune-based treatments for AD are described, including those targeting microglia and T cells. Full article

Canine Cognitive Dysfunction Syndrome (CCDS) is a progressive neurodegenerative disease affecting older dogs that shares many pathological mechanisms with human Alzheimer’s disease (AD). Although it is common in geriatric dogs, CCDS is often underdiagnosed in veterinary medicine. Both CCDS and AD involve a gradual decline in cognitive functions such as memory, learning and executive abilities. From a pathological perspective, dogs with CCDS show brain changes similar to those seen in AD, including cerebral atrophy, loss of neurons and accumulation of amyloid-beta plaques. CCDS is diagnosed by exclusion, meaning that other medical or neurological conditions that could cause similar behavioural signs must first be ruled out. Clinical evaluation mainly relies on structured questionnaires completed by owners. Magnetic resonance imaging is used to confirm cerebral atrophy and, at the same time, to exclude other brain disorders, such as cerebrovascular accidents and neoplasia. Current research focuses on identifying fluid biomarkers, such as amyloid-beta, neurofilament light chain and glial fibrillary acidic protein, to support an early and objective diagnosis. The most effective management combines pharmacological therapy, targeted nutrition and non-pharmacological strategies, including environmental enrichment and behavioural support. Early intervention, ideally during mild cognitive impairment, is crucial to slow disease progression and maintain quality of life. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory decline, cognitive impairment, and behavioral changes, ultimately leading to a loss of independence and reduced quality of life. Although understanding of the molecular basis of AD has advanced, effective disease-modifying therapies remain scarce. Neuropeptides are small protein-like signaling molecules that regulate diverse physiological processes, including mood, memory, and neuronal function. Growing evidence indicates that neuropeptides are promising therapeutic candidates for AD, particularly through modulation of neuroinflammation, synaptic plasticity, and amyloid-beta (Aβ) aggregation. Preclinical AD models show that neuroprotective neuropeptides, such as neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP), exert neuroprotective effects, enhance memory, and attenuate cognitive decline. This review summarizes current research on neuropeptide-based therapies for AD, detailing their molecular mechanisms, therapeutic actions, and the barriers to their clinical translation. We specifically highlight neuropeptides whose clinical potential in AD remains comparatively underrecognized, discuss strategies for optimizing their delivery and overcoming pharmacokinetic limitations, and outline future perspectives for integrating neuropeptide-based interventions into AD therapy. Full article

Systemic autoimmunity plays an important role in pathogenesis of neurodegenerative diseases. The objective of our study was to explore the seroprevalence of naturally occurring autoantibodies (Aabs) targeting a panel of 14 antigens broadly involved in neurodegenerative diseases such as Alzheimer’s Disease, Parkinson’s Disease, frontotemporal dementia, and vascular dementia. Commonly associated proteins with underlying neuronal pathology of the brain include amyloid-beta (Aβ), tau, alpha-synuclein (α-syn), TDP-43, and FUS. Proteins associated with glial and astrocytic involvement—TREM2 and Chi3Li; proteins related to myelin damage and axonal degeneration—light neurofilaments (NFL), myelin basic protein (MBP); synaptic loss reflected by neurogranin (NRGN), a marker of neuronal injury—neuron specific enolase (NSE); and markers of disturbed calcium homeostasis—VSNL1 and neuroinflammation—MCP-1. Presence and levels of plasma IgG against these antigens were examined using enzyme-linked immunosorbent assay (ELISA) method in patients with dementia, patients with mild cognitive impairment (MCI), and healthy age-matched controls. Aabs against all selected antigens were detected across all groups, including healthy control, with varied seroprevalence levels. For the first time, we report the presence of anti-FUS, anti-TREM2, anti-NRGN, anti-VSNL1, anti-NSE, and anti-MCP1 Aabs. Elevated anti-Chi3Li Aabs in individuals with MCI indicate a disease-associated immune signature linked to early neurodegenerative processes. Overall, these results provide evidence of systemic immune activation accompanying neurodegeneration, underscore the complexity of immune involvement, and highlight the importance of targeting multiple pathological pathways in future immunomodulatory strategies. Full article

Background: Alzheimer’s disease (AD) remains an incurable disorder with severe clinical consequences. The type 3 diabetes hypothesis posits that AD may constitute a neuroendocrine disorder driven by disrupted insulin and insulin-like growth factor signaling. Amyloid pathogenesis in AD is characterized by the accumulation of beta-amyloid (Aβ) monomers, their subsequent oligomerization, and amyloid deposition. One of the causes of Aβ accumulation is disruption of amyloid precursor protein (APP) processing due to imbalance in ADAM10 and BACE1 expression. In recent years, increasing attention has been devoted to investigating the role of environmental factors in AD pathogenesis. The receptor for advanced glycation end products (RAGE) serves as a key molecular link between environmental exposure and neuroinflammatory pathology. Formaldehyde (FA) is one of the most widespread environmental pollutants. Its involvement in amyloid plaque formation has been previously reported; however, the molecular mechanisms underlying this process remain insufficiently understood. Moreover, most available data are based on prolonged FA exposure, whereas industrial FA emissions are often short-term. The objective of this study was to determine whether brief intranasal administration of FA, modeling episodic industrial pollution, induces RAGE-mediated neuroinflammation and amyloid deposition in CD1 mice. Methods: Mice received intranasal FA at environmentally relevant 0.02 mg/day or 0.2 mg/day doses for seven days; an additional group was co-treated with insulin. Cognitive function was assessed using passive avoidance (PA) and radial arm maze (RAM) tests, and synaptic plasticity was evaluated by electrophysiology. Hippocampal tissue was analyzed for RAGE expression, ADAM10/BACE1 gene balance, Aβ42 monomer levels, and amyloid deposits using optimized Thioflavin-S (Th-S) staining. Results: We observed cognitive decline in mice receiving intranasal FA administration. Elevated blood glucose levels were also observed following intranasal FA exposure. Sustained impairment of glucose metabolism led to overexpression of the RAGE in the hippocampus. There was also an imbalance of ADAM10 and BACE1 expression in the hippocampus. This was caused by overexpression of RAGE, as the enhanced interaction of the ligand and RAGE is a key factor disrupting this balance. Finally, Th-S staining confirmed amyloid deposition in mice subjected to intranasal FA exposure. Conclusions: This study provides new insights into the RAGE-mediated mechanisms by which FA contributes to the pathogenesis of AD. Full article

The cytotoxic effect of islet amyloid polypeptide (IAPP) misfolding and aggregation has a well-recognized role in the pathogenesis of type 2 diabetes mellitus, mediated by failure of the beta cell’s protein quality control system to rescue the cell from overwhelming proteotoxic stress induced by IAPP aggregates, ultimately leading to apoptosis. A small but growing body of research also links IAPP-mediated proteotoxic stress to the pathogenesis of type 1 diabetes and to the functional decline of transplanted islets. Among the most promising therapeutic approaches under investigation are small organic molecules that may act as direct chemical chaperones to prevent IAPP aggregation, promote the activity of endogenous chaperones, or alter gene networks of the unfolded protein response (UPR) to promote pro-survival rather than pro-apoptotic pathways in response to IAPP-mediated proteotoxic stress. Compounds warranting special attention include 4-phenylbutyrate (PBA), tauroursodeoxycholic acid (TUDCA), and epigallocatechin gallate (EGCG), as each has a growing body of evidence supporting their ability to ameliorate this process, and given that each of these are already known to have good safety profiles in humans, potentially accelerating the timeline to interventional studies. This review explores the evidence for IAPP-mediated proteotoxicity in multiple forms of diabetes, the mechanisms of cytotoxicity at different levels of the cell’s protein quality control systems, how these small organic compounds may act on these processes including new insights on the role of thioredoxin-interacting protein (TXNIP), and the current evidence supporting each of these compounds in mitigating diabetogenesis. Full article