Search Results (595)

Emerging evidence suggests that systemic physiological factors may influence plasma biomarker concentrations of Alzheimer’s disease (AD) and related neurodegenerative processes, potentially affecting their specificity for central nervous system pathology. This study examined the relationship of demographic factors and medical comorbidities with plasma biomarkers of AD and neurodegeneration in a community-dwelling cohort of Black/African American (B/AA) older adults (N = 141). Participants underwent plasma assessment of phosphorylated tau at threonine 217 (p-Tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Results showed associations between plasma p-Tau217 and amyloid PET positivity, and significant intercorrelations among p-Tau217, GFAP, and NfL. Stepwise regression models incorporated demographics, amyloid PET status, and laboratory measures of renal, metabolic, and lipid function as predictors for each biomarker. p-Tau217 was primarily predicted by amyloid PET and renal function; GFAP by age and sex; and NfL by renal function, age, and sex. Findings indicate plasma biomarker concentrations in B/AA older adults reflect both central AD-related pathology and systemic physiological factors, particularly renal function, and demographic influences. Results underscore the importance of accounting for comorbid medical conditions and demographic characteristics when interpreting blood-based biomarkers and highlight the need for comprehensive medical phenotyping to improve diagnostic specificity and clinical utility. Full article

Tauopathies, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal lobar degeneration with tau pathology, are unified by pathogenic tau misfolding, post-translational modification, aggregation, and network-level spread. Yet decades of drug development that predominantly pursued single nodes (e.g., one kinase, one aggregation inhibitor, one monoclonal antibody epitope) have repeatedly delivered late-stage disappointments, underscoring a central lesson: tauopathy behaves less like a linear pathway and more like a coupled system of proteostasis failure, neuroinflammation, synaptic-mitochondrial stress, and metabolic dysregulation. This review examines rhizomes (notably Zingiberaceae genera such as Curcuma, Zingiber, Alpinia, Kaempferia, and Boesenbergia) as chemically diverse “multi-target platforms” whose bioactives can engage several tau-relevant nodes simultaneously. We synthesise evidence across tau phosphorylation (GSK-3β/CDK5 and upstream stress signalling), tau aggregation and seeding, autophagy-lysosome and proteasome pathways, redox-mitochondrial resilience, neuroinflammatory circuits (NF-κB/NLRP3), and neuro-metabolic signalling (insulin-PI3K-AKT, AMPK-mTOR). A translational lens is applied throughout, focusing on drug-likeness and CNS multiparameter optimisation; BBB permeability and efflux; metabolism and bioavailability constraints; and formulation strategies (nanoparticles, phytosomes, engineered exosomes) that may render rhizome-derived scaffolds more clinically plausible. We conclude that rhizomes offer credible mechanistic hypotheses for tau modulation, but progress depends on rigorous standardisation, realistic exposure matching, biomarker-driven study design, and a shift from “single-compound optimism” to network pharmacology with translational discipline. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. Its main pathological features are extracellular plaques composed of aggregated amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles formed by hyperphosphorylated tau. The Aβ hypothesis proposes that Aβ accumulation is a key driver of AD, influencing tau pathology, neuroinflammation, and neurodegeneration. However, therapies that reduce Aβ have shown limited clinical benefits. This suggests that the mechanisms underlying peptide-mediated modulation of AD pathology are much more complex. Both Aβ and tau undergo various post-translational modifications (PTMs) that affect their structure, aggregation, and toxicity. In addition, these abnormal proteins are not efficiently cleared in AD, indicating dysfunction of the protein quality control (PQC) system that maintains proteostasis. Such abnormal PTMs and impaired PQC likely work together to drive disease progression, which may explain the limited success of Aβ-reduction therapies. In this review, we describe how major PTMs, including phosphorylation, ubiquitination, acetylation, glycosylation, and oxidation, regulate the pathological behavior of Aβ and tau. We also discuss the role of the PQC systems in the pathology of AD. We propose that dysregulation of PTMs and PQC constitutes a convergent mechanism underlying AD pathogenesis. Therapeutic strategies targeting these processes may provide more effective and sustained disease modification than approaches focused solely on Aβ reduction. Full article

Alzheimer’s disease (AD) is a neurodegenerative disease impacting over 6 million Americans, with cases projected to increase to over 14 million by 2060. The AD pathology leads to difficulty completing everyday tasks or conversations, and ultimately, progresses to disrupt the most basic bodily functions and require full-time caretaking. While disease-modifying therapy remains elusive, reducing the incidence of AD is crucial to mitigate the projected increase in cases. Exercise has emerged as an effective strategy to promote brain health in late adulthood and to protect against the onset of AD. Exercise opposes several disease processes, including cognitive dysfunction, amyloid beta aggregation, tau phosphorylation, and deficits in hippocampal volume, mitochondrial function, cerebral blood flow, and neurogenesis, through various pathways, including the systemic release of exerkines. The exerkine irisin is an important mediator of the beneficial relationship between exercise and the brain. Previous work administering irisin therapeutically to healthy and preclinical AD mice has demonstrated irisin use to replicate multiple exercise-induced effects in the brain and protect against AD-induced deficits. Although irisin is suggested as a promising strategy for promoting brain health in late adulthood, our understanding of irisin signaling and its protective effects against AD remains incomplete. This review will investigate irisin as an important, physiologically relevant promoter of brain health in aging and AD. Full article

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

Background: Vascular dysfunction and neurovascular inflammation are increasingly recognized as contributors to Alzheimer’s disease (AD) pathophysiology, particularly through interactions with tau-related neurodegeneration. Endothelial adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), play key roles in blood–brain barrier regulation and immune-vascular crosstalk, yet their relevance to long-term disease progression and established AD biomarkers remains incompletely understood. Methods: Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we examined associations between baseline cerebrospinal fluid (CSF) levels of VCAM-1 and ICAM-1 and clinical progression, CSF biomarkers, neuroimaging measures, and cognitive outcomes over up to 10 years of follow-up. This study included 294 participants (87 cognitively normal, 129 with mild cognitive impairment, and 78 with AD). Multivariable logistic regression was used to assess associations with diagnostic progression, and linear regression models examined relationships with baseline and longitudinal measures of tau, amyloid-β, hippocampal volume, Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) metabolism, and cognition. Models were adjusted for age, sex, apolipoprotein E epsilon 4 (APOE ε4) status, baseline diagnosis, and baseline CSF amyloid-β, with false discovery rate correction applied for multiple comparisons. Results: Baseline CSF VCAM-1 and ICAM-1 levels did not differ across diagnostic groups. However, higher baseline levels of both markers were nominally associated with increased odds of disease progression. Notably, ICAM-1 showed a strong and robust association with baseline CSF phosphorylated tau, which remained significant after multiple-comparison correction. VCAM-1 was also associated with tau pathology, though this did not survive correction. Neither marker was associated with baseline or longitudinal changes in hippocampal volume, FDG-PET metabolism, or cognitive performance. Conclusion: CSF VCAM-1 and ICAM-1 appear to reflect neurovascular inflammatory processes linked to tau pathology rather than markers of clinical stage or longitudinal neurodegeneration. These findings support a role for endothelial activation in AD pathophysiology and highlight vascular–immune mechanisms as potential contributors to tau-related disease vulnerability. Full article

Background/Objectives: Currently available treatments approved by the Food and Drug Administration for Alzheimer’s disease (AD) either only target the symptoms of AD or, if disease-modifying, have severe side effects. This study aims to explore the potential of the FDA-approved Rho-associated kinase (ROCK) inhibitor netarsudil to reduce tau, a pathological protein in AD. Methods: We explored the pharmacokinetic and pharmacodynamic properties of netarsudil following a single intraperitoneal (i.p.) injection in wild-type mice. The efficacy of netarsudil was assessed using ELISA targeting tau/phosphorylated tau (ptau), as well as mass spectrometry-based proteomics. Results: We found that netarsudil is brain permeable, reaches peak concentrations rapidly and has moderate but sustained exposure in the central nervous system (CNS). Additionally, there was a statistically significant negative association between brain netarsudil exposure and tau and phosphorylated tau at residue 181 (ptau181). The exploratory proteomic analysis of mouse brains exposed to netarsudil revealed changes in mitochondrial function, enrichment of metallothioneins Mt1 and Mt2, and suppression of the AD-related genes Pzp and Serpina3m. Conclusions: The apparent reduction in AD pathological protein tau/ptau and a neuroprotective proteomic profile in vivo suggest the potential for netarsudil to be developed as a new AD therapeutic agent. Full article

Tau hyperphosphorylation is a hallmark of tauopathies and is closely associated with neurodegeneration. While targeting kinases and phosphatases to suppress tau phosphorylation has become an increasingly attractive therapeutic approach, the functional significance of tau phosphorylation and the potential risks of suppressing this process are not fully understood. Using C. elegans, we introduced non-phosphorylatable tau mutations (hTauAP) to model the suppression of tau phosphorylation. Unexpectedly, we found that hTauAP induced severe neurotoxicity, resulting in behavioural deficits and severe neurite abnormalities. This neurotoxicity is associated with excessive accumulation of hTauAP on microtubules, leading to both neurite developmental defects and adult neurite degeneration. The neurotoxic effects of hTauAP require its microtubule-binding domain (MTB) and are primarily driven by the loss of phosphorylation in the C-terminal region (CTR). Removing either domain reduces microtubule association and suppresses toxicity. Within CTR, suppressing phosphorylation at S396 or S404 is critical for neurotoxicity. These findings highlight the essential role of tau phosphorylation in neuronal function and underscore the potential risks of broadly suppressing tau phosphorylation as a therapeutic strategy. Full article

Background and clinical significance: Autoimmune encephalitis (AE) is an inflammatory brain disorder that manifests through a diverse, unspecific range of neuropsychiatric symptoms. When AE occurs alongside a primary neurodegenerative disorder, the shared symptoms can create a mixed clinical profile, making diagnosis more difficult and potentially postponing effective management and treatment. Case presentation: We describe the case of a 58-year-old female with a one-year history of progressive behavioral and personality changes who presented a subacute confusional state, psychomotor retardation alternating with psychomotor agitation, apathy, visual hallucinations, and motor symptoms. Examination revealed Parkinsonian symptoms and frontal lobe signs. Neuroimaging showed frontotemporal atrophy, while cerebrospinal fluid analysis excluded infection but demonstrated elevated phosphorylated tau, supporting an underlying neurodegenerative process. An electroencephalogram revealed asymmetric temporal slowing without overt epileptiform activity. An initial diagnosis of behavioral variant frontotemporal dementia (bvFTD) was established. Due to rapid clinical deterioration and fluctuating cognition, autoimmune testing was expanded to a full antibody panel, which identified elevated serum anti-glutamic acid decarboxylase 65 (anti-GAD65) antibodies (60 UI/mL, reference range 0–5 UI/mL), establishing a possible coexisting diagnosis of anti-GAD65 autoimmune encephalitis. Initial treatment with intravenous immunoglobulin produced minimal improvement; however, therapeutic plasma exchange led to the remission of psychosis and significant improvement in rigidity, bradykinesia, and attention, with modest amelioration in global cognition. Conclusions: This case highlights the diagnostic challenges posed by overlapping AE and bvFTD clinical pictures, especially when neurodegenerative features obscure an underlying autoimmune process. Early, panel-based neural antibody testing—and consideration of AE even in patients already diagnosed with a major neurocognitive disorder—is critical for avoiding delays in immunotherapy. Prompt recognition and treatment of AE may substantially improve clinical outcomes, even in complex cases with suspected overlap. Full article

Mitochondrial dysfunctions contribute to the pathogenesis of tauopathies, a group of neurodegenerative diseases with abnormal accumulation of microtubule-associated protein tau. The combination of 5-aminolevulinic acid (5-ALA) and sodium ferrous citrate (SFC) is known to improve mitochondrial functions. Here, we report that 5-ALA combined with SFC (5-ALA/SFC) improves mitochondrial functions and mitigates neurodegeneration in transgenic Drosophila expressing human tau. We found that tau reduces ATP levels, decreases mitochondrial distribution to neurites, and increases mitochondrial reactive oxygen species (ROS). Expression of oxidative phosphorylation (OXPHOS) genes was upregulated, and activities of complexes I and IV were elevated. Feeding 5-ALA/SFC to tau flies lowers oxidative damage without correcting OXPHOS activities or mitochondrial distribution. 5-ALA/SFC treatment suppressed pathological tau phosphorylation and mitigated tau-induced neurodegeneration. These results suggest that 5-ALA/SFC attenuates a neurodegenerative pathway involving tau, mitochondria, and ROS. Full article

Progressive supranuclear palsy-Richardson’s syndrome (PSP-RS) is a primary 4R tauopathy in which early axonal dysfunction may precede overt neurodegeneration; however, the mechanisms linking Tau dysregulation to cytoskeletal vulnerability remain poorly defined. Here, we generated induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic neurons from individuals with sporadic PSP-RS and matched healthy controls and performed integrated transcriptomic and proteomic analyses. PSP-RS neurons exhibited coordinated suppression of dopaminergic and synaptic programs alongside activation of cytoskeletal remodeling and stress-related pathways. These changes were accompanied by increased Tau phosphorylation, neurofilament accumulation, and structural alterations of the axonal compartment, consistent with an early axonopathic phenotype. Notably, mechanistic target of rapamycin (mTOR) signaling significantly increased. Pharmacological inhibition of mTOR reduced Tau phosphorylation and neurofilament levels, indicating that mTOR activity contributes to the maintenance of cytoskeletal imbalance. In conclusion, our findings support a model in which early cytoskeletal dysfunction in PSP-RS arises from the convergence of Tau dysregulation, impaired structural homeostasis, and altered signaling pathways. Rather than acting as a primary driver, mTOR appears to function as a pathogenic amplifier that sustains axonal stress. This study provides a human cellular framework to investigate early axonopathic mechanisms in sporadic PSP-RS. 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

Mitochondria are essential organelles that perform irreplaceable functions in neurons. The degeneration of neurons in Alzheimer’s disease (AD) is associated with mitochondrial damage, and Tau pathology represents a significant pathogenic factor in AD. However, the relationship between Tau and mitochondrial dysfunction during neuronal degeneration remains unclear. In this study, we investigated the effects and mechanisms by which extracellular Tau aggregates induce neuronal mitochondrial damage and dysfunction. The results showed that extracellular Tau aggregates lead to structural damage of mitochondria in SH-SY5Y cells and disrupt mitochondrial homeostasis. Extracellular Tau aggregates can also cause mitochondrial oxidative stress and inhibit oxidative phosphorylation in SH-SY5Y cells. Concurrently, extracellular Tau aggregates promote neuronal death through an increase in cytochrome C, mtDNA leakage and activation of the cGAS/STING pathway. We also explored the effects of a single-chain variable fragment antibody (scFv T1) and found that scFv T1 alleviated mitochondrial damage and dysfunction by inhibiting the formation of Tau aggregates. These findings suggest that targeting Tau pathology may be crucial to address neuronal mitochondrial impairment and that reduction of the toxicity associated with extracellular Tau aggregates could help slow Tau pathology progression. Full article

Objective: This study aims to investigate the protective effect of Shengmai San (SMS) against high-glucose (HG)-induced injury in neonatal rat ventricular myocytes (NRVMs) and to elucidate the underlying pharmacological molecular mechanisms. We hypothesize that SMS ameliorates HG-induced calcium homeostasis imbalance in NRVMs by improving mitochondrial energy metabolism disorder, and this protective effect is associated with the downregulation of oxidized and phosphorylated CaMKII expression to inhibit CaMKII signaling pathway overactivation. Herein, we verify this hypothesis by assessing mitochondrial function, calcium transients, sarcoplasmic reticulum (SR) calcium handling and CaMKII phosphorylation levels in NRVMs. Methods: First, ultra-high performance liquid chromatography–high resolution mass spectrometry was used to identify the chemical components of SMS to clarify its material basis. Primary NRVMs were then cultured under low-glucose (LG) or HG conditions, with 2% SMS-medicated serum (SMS-MS) as the experimental intervention, and NAC (ROS scavenger) and KN93 (CaMKII inhibitor) as positive controls. Following intervention, we sequentially detected key indicators corresponding to the proposed pathological pathway: intracellular reactive oxygen species (ROS) levels (oxidative stress), mitochondrial ROS, mitochondrial function indices including oxygen consumption rate (OCR) (energy metabolism), calcium transients and diastolic intracellular free calcium concentration (global calcium homeostasis), sarcoplasmic reticulum (SR) calcium leak (calcium handling disorder), and, finally, the phosphorylation, oxidation levels of CaMKII and RyR2 phosphorylation (Ser2814) (p-RyR2) (key regulatory pathway) via Western blot to systematically elucidate the mechanistic link between SMS intervention and HG-induced NRVM injury. Results: Quantitative analysis revealed that high-glucose (HG) induction significantly reduced calcium transient amplitude and prolonged the decay time constant (tau) in NRVMs at 72 h (p < 0.01 vs. LG), with these parameters normalizing by 120 h—an effect indicative of a compensatory adaptive response. The 2%SMS-MS markedly ameliorated HG-induced calcium transient abnormalities at 72 h (p < 0.01 vs. HG). Additionally, 2%SMS-MS significantly enhanced mitochondrial basal oxygen consumption rate, spare respiratory capacity, ATP production, and maximal respiration in HG-exposed NRVMs (p < 0.01 vs. HG). SMS also significantly reduced intracellular reactive oxygen species (ROS) levels (p < 0.01 vs. HG), mitochondrial ROS levels (p < 0.01 vs. HG), diastolic intracellular free calcium concentration (p < 0.01 vs. HG), and SR calcium leak (p < 0.05 vs. HG). Western blot analysis revealed that 2%SMS-MS intervention effectively downregulated the expression of oxidized CaMKII (Ox-CaMKII) (p < 0.01 vs. HG), phosphorylated CaMKII (p-CaMKII) (p < 0.01 vs. HG), and RyR2 phosphorylation (Ser2814) (p < 0.05 vs. HG), which may be the potential mechanism in maintaining calcium homeostasis in HG-induced NRVMs. Conclusions: This study suggests that SMS enhances mitochondrial energy metabolism and exerts a protective effect against high-glucose-induced calcium homeostasis imbalance in NRVMs, which supports our proposed hypothesis. Its potential mechanism indicates that the protective effects of SMS are associated with its ability to downregulate the expression of oxidized and phosphorylated CaMKII. These findings highlight SMS as a potential therapeutic candidate for alleviating HG-related myocardial injury and provide evidence for its application in the prevention of early diabetic cardiomyopathy. Full article

The 3-nitropropionic acid (NPA) promotes neurological alterations in the striatum, hippocampus and vicinal motor and pre-motor cortical areas, and in the cerebellum. The neurological alterations induced by systemic NPA administration resemble those found in Huntington’s disease. In previous works, we have shown that intraperitoneal (i.p.) administration of kaempferol can efficiently protect against striatum degeneration and against motor neurological dysfunctions induced by NPA. In this work, we show that i.p. administration of kaempferol also protects against the increase in pro-inflammatory cytokines that potentiate the activation of complement C3 protein (a biomarker of A1-type reactive astrocytes generation) and overproduction of neurotoxic amyloid β (Aβ) peptides in the cerebellum of rats treated with acute i.p. administration of NPA. In NPA-treated rats, large multipolar neurons of cerebellar nuclei and Purkinje neurons of the cerebellar cortex are the cells that are most intensely stained by anti-C3 and by anti-Aβ antibodies. In addition, we found that kaempferol also protects against the NPA-induced increase in phospho-tau 217 and phospho-tau 181 in the cerebellum, and our results pointed out that the NPA-induced phospho-tau 217 colocalizes with Aβ(1-42) more closely than phospho-tau 181, both in dentate nucleus and cerebellar cortex. Also, our results unveil another novel brain-protective action of i.p. kaempferol co-administration: namely, its ability to prevent microhemorrhages induced in the cerebellar nuclei area by acute NPA administration. In conclusion, the results of this work show a potent protection of kaempferol against the NPA-induced increase in degeneration biomarkers in the cerebellum. Full article