Salvianolic acid a inhibits neuroinflammation and ameliorates Alzheimer's disease pathology via the p38 MAPK/NF-κB pathway based on network pharmacology and experimental validation.

Nitric Oxide Signaling in Alzheimer's Disease: A Double-Edged Sword.

Parkinson's disease (PD) is a common neurodegenerative disorder affecting middle-aged and elderly individuals. Its clinical manifestations include both motor and non-motor symptoms. Traditionally, Lewy bodies (LBs), which are formed by misfolded α-synuclein (α-syn), have been regarded as the core pathological hallmark. It is believed that the selective damage to dopaminergic neurons in the nigrostriatal system by LBs constitutes the primary mechanism underlying motor symptoms. However, approximately 30-80 % of PD patients also experience psychiatric and behavioral disturbances, such as anxiety, depression, cognitive impairment, and sleep disorders. The pathological mechanisms underlying these symptoms cannot be fully explained by α-syn alone. Recent biomarker studies have confirmed that hyperphosphorylated tau protein forms neurofibrillary tangles (NFTs) and amyloid β-protein (Aβ) plaques can coexist with α-syn in the brains of PD patients, especially in advanced stages. These coexisting pathologies show significant positive correlations with cognitive impairment and sleep disorders, suggesting that the neuropsychiatric symptoms in PD may result from the synergistic effects of multiple protein pathologies involving α-syn, tau, and Aβ. This review synthesizes these findings to propose an integrated "synergistic co-pathogenic network" of α-syn, tau, and Aβ, thereby providing a novel theoretical framework for developing precise, multi-target therapeutic strategies against PD-related neuropsychiatric disorders.

Aluminum chloride in Alzheimer's disease: A dual focus on molecular mechanisms and rat experimental models.

Gentisic acid confers multimodal neuroprotection in experimental Alzheimer's disease by targeting oxidative stress, neuroinflammation, and protein aggregation.

Tau protein hyperphosphorylation and neuroinflammation playimportant roles in the onset and progression of Alzheimer's disease (AD). SIRT1has been implicated in the regulation of synaptic plasticity, cognitive function, andmemory, and is associated with the modulation of autophagy-and inflammation-related signaling pathways, including AMPK/mTOR/ULK1 and NF-κB. Resveratrol(RSV) has been reported to ameliorate cognitive impairment in AD models,primarily in the context of Aβ-related pathology; however, its potential effects andunderlying mechanisms in Tau-driven pathology remain incompletely understood. To investigate the effect of RSV on cognitive impairment in mice withTau mutation-induced Alzheimer's disease, and to explore its effects on autophagyand neuroinflammation. Tauopathy models were established using AAV-P301L-Tau. Cognitivefunction was assessed via behavioral tests; Hippocampal injury was evaluatedAccepted manuscriptACCEPTED MANUSCRIPTusing HE and Nissl staining, while autophagy was assessed byimmunofluorescence staining. Mechanisms were examined using Western blot,qRT-PCR, and CCK-8 assays. RSV treatment was associated with attenuation of neuronal damage,reduction of p-Tau accumulation, and improvement of cognitive impairment in ADmice. Consistent trends were observed in vitro, where RSV treatment wasassociated with increased cell viability and modulation of autophagy-relatedmarkers in AAV-P301L-Tau-induced BV2 cells. In addition, RSV administration wasaccompanied by coordinated changes in signaling components related to SIRT1,AMPK/mTOR/ULK1, and NF-κB pathways, along with reduced expression ofinflammatory mediators. RSV treatment was associated with coordinated modulation ofsignaling components related to the AMPK/mTOR/ULK1 and NF-κB pathways,together with improvements in cognitive performance in AD mice. These findingssupport the potential therapeutic relevance of RSV in Tau-drivenneurodegenerative pathology, while further studies are required to clarify theunderlying mechanisms.

An integrative proteomic approach to reveal altered signaling modules during Alzheimer's disease progression in PS19 tauopathy mice.

Neuroimmune dysregulation in Alzheimer's disease: Mechanisms and therapeutic strategies.

Discovery and structure-activity relationship of cannabidiol aminoquinones as anti-Alzheimer's agents via dual modulation of Nrf2/HO-1 and TLR4/NF-κB pathways.

Alzheimer's disease (AD) is characterized by pathological hyperphosphorylation of TAU protein, leading to neurofibrillary tangle formation, synaptic dysfunction, neuroinflammation, and neuronal loss. Hexaraphane (6-(methylsulfinyl) hexyl isothiocyanate; HXN), a bioactive compound derived from Wasabia japonica, exhibits neuroprotective and anti-inflammatory properties, yet its potential role in tauopathies remains unknown. Here, we investigated whether HXN modulates pathological TAU phosphorylation and explored the underlying mechanisms in vitro and in vivo. Using primary neurons from APP/TAU transgenic mice with either NRF2 wild-type or knockout backgrounds, combined with complementary genetic and pharmacological approaches, we found that HXN markedly reduced pathological phospho-TAU epitopes (AT8 and PHF1). Notably, this effect occurred independently of NRF2 signaling. Mechanistically, HXN did not suppress GSK-3β activity or alter upstream PI3K/AKT or MAPK pathways. Instead, pharmacological inhibition experiments and phosphatase assays demonstrated that HXN promotes PP2A-dependent TAU dephosphorylation, identifying phosphatase activation as a central mechanism of action. Chronic oral administration of HXN in APP/TAU mice led to significant reductions in brain phospho-TAU levels across multiple regions and decreased blood circulating TAU-pThr217 concentrations. These molecular changes were accompanied by attenuation of neuroinflammatory markers, preservation of neuronal integrity, restoration of synaptic plasticity, and improvements in cognitive and motor performance. Collectively, our findings identify HXN as a potent modulator of pathological TAU phosphorylation. These results support the development of HXN as a promising disease-modifying therapeutic strategy for AD and other TAU-driven neurodegenerative disorders.

Alzheimer's disease (AD) is a severe form of dementia, which occurrence increases with age and lifestyle conditions. It is characterized by amyloid protein accumulation forming senile plaques, hyperphosphorylated tau protein forming neurofibrillary tangles, neuroinflammation, and oxidative stress, leading to synapse loss and cell death. Pharmacological alternatives to conventional treatments include alkaloids with anti-inflammatory and antioxidant properties. Sesquiterpene lactones, such as Xanthatin-13-(pyrrolidine-2-carboxylic acid) (XPc) from burdock leaf, show promise due to their antioxidant activity targeting glucose-6-phosphate dehydrogenase. This study evaluated XPc's protective effects invivo using Aβ25-35-treated mice, a pharmacological AD model, and explores its synergistic potential with neuroprotective agents like TSPO activators or sigma-1 receptor agonists. Mice were administered Aβ25-35 peptide (9 nmol ICV) and XPc (0.3-3 mg/kg) daily for 4 days. Behavioral tests assessed memory deficits and anxiety. Post-sacrifice, brains were analyzed for neuroinflammation and oxidative stress markers. Combination studies involved XPc with the TSPO activator PK11195 or the sigma-1 receptor agonist PRE-084, with memory evaluated in two behavioral tests. Combination indices were calculated to assess synergy. XPc (1-3 mg/kg) prevented Aβ25-35-induced memory impairments and anxiety. It reduced astroglial reaction, blocked microglial activation, and confirmed antioxidant activity by lowering lipid peroxidation and protein nitrosylation. Combinations with PK11195 or PRE-084 showed synergistic protection in memory tests. XPc is a potent neuroprotective agent against AD-like toxicity in this murine model, effective alone or in synergistic combinations with other drugs.

According to the prevalent 'Amyloid Hypothesis,' the underlying cause for neurodegeneration in Alzheimer Disease (AD) is attributed to the accumulation of misfolded Amyloid ß and tau protein in the form of extracellular sticky plaques and neurofibrillary tangles, respectively. These protein accumulations are thought to be caused by impaired waste removal. In an alternative hypothesis, we have proposed the existence of an extensive glial canal system that is likely formed by myelinated aquaporin-4 (AQP4)-expressing tanycytes and removes cellular waste from the hippocampal formation. Here, we demonstrate that tanycyte-derived waste-internalizing receptacles are immunoreactive for Aß and emanate from specialized nucleus-like organelles in the following referred to as 'tanysomes.' Utilizing RNA-scope in situ hybridization, we demonstrate that these receptacle-forming tanysomes express RNA for AQP4 and the Aß-related genes, amyloid precursor protein, and presenilin-1. These findings suggest that Aß is likely synthesized where receptacle formation is observed and that Aß may play an important structural role in receptacle formation. In AD-affected hippocampus, excessive amounts of Aß-immunoreactive waste receptacles emerge from tanysomes and have the appearance of plaques in Aß-immunolabeled hippocampus. Moreover, we demonstrate that the same receptacle-forming organelles exhibit strong immunolabeling for hyperphosphorylated tau protein in AD-affected tissue. We postulate that both proteins may play important structural roles in waste uptake and that hypertrophic swelling of impaired tanycytes in AD-affected brain may be due to obstructions of this extensive interconnected glial canal system.

Icariin Promotes Lysosomal Degradation of Amyloid-β Precursor Protein via Enhanced Endosome-Lysosome Trafficking to Reduce Amyloid-β Accumulation and Improve Cognitive Function in Alzheimer's Disease Models.

BackgroundInflammatory factors are widely recognized as contributors to Alzheimer's disease (AD), along with pathological changes in amyloid-β (Aβ) and tau proteins.ObjectiveWe aimed to determine whether sex influences the inflammation-related cognitive performance.MethodsThis cross-sectional study included 317 patients (260 cognitively impaired and 57 cognitively normal) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) between September 7, 2005, and August 7, 2024. Interaction analysis was used to examine sex-specific effects of interleukins, while logistic regression examined associations between interleukins and clinically relevant worsening on non-memory Mini-Mental State Examination (MMSE) items (BCNMMMS). Linear regression assessed associations with hyperphosphorylated tau proteins (P-tau181). Finally, mediation analysis was conducted to investigate the role of sex hormone-binding globulin (SHBG) in interleukins, BCNMMMS, and P-tau181.ResultsIn BCNMMMS, sex interactions were observed for IL-1β (p = 0.048), IL-21 (p = 0.020), and complement component 3 (C3) (p = 0.041). After adjustment for confounding factors, IL-18 was associated with BCNMMMS in males (OR = 0.520 [0.274, 0.983]), while C3 was associated with BCNMMMS in females (OR = 0.452 [0.215, 0.950]). IL-21 and C3 levels were significantly associated with P-tau181 in females (IL-21: p = 0.002, C3: p = 0.047) but not in males. Besides, SHBG mediated the effect of IL-21 on cognitive performance in females (proportion of mediation = 19.72%; p = 0.032), suggesting a role for SHBG in sex-dependent inflammatory pathways related to cognitive performance.ConclusionsPeripheral inflammatory biomarkers, particularly IL-21, showed sex-specific links to plasma P-tau181 and non-memory impairment in ADNI, supporting sex-stratified analyses.

From mechanisms to therapeutics: The expanding role of cell-based strategies in Alzheimer's disease.

Choline serves as the primary active compound of anti-aging tablets and targets PTGS2 to alleviate neuronal damage in Alzheimer's disease by modulating ferroptosis and apoptosis in nerve cells.

ELAVL1 interacts with APP and promotes Aβ-induced apoptosis in Alzheimer's disease by activating Bcl-2/Bax signaling.

Advances in neural mechanisms and magnetic resonance imaging biomarkers of aluminum exposure causing cognitive impairment.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by β-amyloid deposition, hyperphosphorylated tau protein, and progressive neuronal loss. Mitochondria form a dynamic interconnected network within the central nervous system, and their dysfunction plays a central role in AD, involving oxidative stress, kinetic dysregulation, and impaired mitochondrial autophagy. As key mediators of intercellular communication, exosomes carry bioactive components that regulate mitochondrial function in recipient cells. This review summarizes advances in research on exosomes as coordinators of the mitochondrial network in the central nervous system, regulating mitochondrial quality control across different neuronal cell types. It systematically outlines the molecular mechanisms by which exosomes modulate mitochondrial function in AD through regulating mitochondrial biogenesis, fusion-fission dynamics, mitochondrial autophagy, and related signaling pathways. Furthermore, it explores the potential of engineered exosome-based targeted therapies for AD intervention, aiming to provide a theoretical foundation and research direction for developing novel therapeutic strategies targeting mitochondrial dysfunction.

Targeting the Nrf2/HO-1 aixs: A therapeutic strategy against regulated cell death in Alzheimer's disease.