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Acta Pharmacologica Sinica Jul 2024Abnormal accumulation of hyperphosphorylated tau protein plays a pivotal role in a collection of neurodegenerative diseases named tauopathies, including Alzheimer's...
Abnormal accumulation of hyperphosphorylated tau protein plays a pivotal role in a collection of neurodegenerative diseases named tauopathies, including Alzheimer's disease (AD). We have recently conceptualized the design of hetero-bifunctional chimeras for selectively promoting the proximity between tau and phosphatase, thus specifically facilitating tau dephosphorylation and removal. Here, we sought to optimize the construction of tau dephosphorylating-targeting chimera (DEPTAC) and obtained a new chimera D14, which had high efficiency in reducing tau phosphorylation both in cell and tauopathy mouse models, while showing limited cytotoxicity. Moreover, D14 ameliorated neurodegeneration in primary cultured hippocampal neurons treated with toxic tau-K18 fragments, and improved cognitive functions of tauopathy mice. These results suggested D14 as a cost-effective drug candidate for the treatment of tauopathies.
PubMed: 38956416
DOI: 10.1038/s41401-024-01326-4 -
Nature Communications Jul 2024Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers...
Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers (SORTOUT-AB) is a multi-center longitudinal study to compare AD biomarkers in participants who identify their race as either Black or white. Plasma samples from 324 Black and 1,547 white participants underwent analysis with CN Diagnostics' PrecivityAD test for Aβ42 and Aβ40. Compared to white individuals, Black individuals had higher average plasma Aβ42/40 levels at baseline, consistent with a lower average level of amyloid pathology. Interestingly, this difference resulted from lower average levels of plasma Aβ40 in Black participants. Despite the differences, Black and white individuals had similar longitudinal rates of change in Aβ42/40, consistent with a similar rate of amyloid accumulation. Our results agree with multiple recent studies demonstrating a lower prevalence of amyloid pathology in Black individuals, and additionally suggest that amyloid accumulates consistently across both groups.
Topics: Humans; Amyloid beta-Peptides; White People; Male; Female; Alzheimer Disease; Longitudinal Studies; Aged; Peptide Fragments; Biomarkers; Black or African American; Middle Aged; Aged, 80 and over; Black People
PubMed: 38956096
DOI: 10.1038/s41467-024-49859-w -
Nature Communications Jul 2024Iron plays a fundamental role in multiple brain disorders. However, the genetic underpinnings of brain iron and its implications for these disorders are still lacking....
Iron plays a fundamental role in multiple brain disorders. However, the genetic underpinnings of brain iron and its implications for these disorders are still lacking. Here, we conduct an exome-wide association analysis of brain iron, measured by quantitative susceptibility mapping technique, across 26 brain regions among 26,789 UK Biobank participants. We find 36 genes linked to brain iron, with 29 not being previously reported, and 16 of them can be replicated in an independent dataset with 3,039 subjects. Many of these genes are involved in iron transport and homeostasis, such as FTH1 and MLX. Several genes, while not previously connected to brain iron, are associated with iron-related brain disorders like Parkinson's (STAB1, KCNA10), Alzheimer's (SHANK1), and depression (GFAP). Mendelian randomization analysis reveals six causal relationships from regional brain iron to brain disorders, such as from the hippocampus to depression and from the substantia nigra to Parkinson's. These insights advance our understanding of the genetic architecture of brain iron and offer potential therapeutic targets for brain disorders.
Topics: Humans; Iron; Brain; Exome Sequencing; Male; Female; Mendelian Randomization Analysis; Genome-Wide Association Study; Parkinson Disease; Middle Aged; Genetic Predisposition to Disease; Aged; Nerve Tissue Proteins; Adult; Alzheimer Disease
PubMed: 38956042
DOI: 10.1038/s41467-024-49702-2 -
ACS Applied Materials & Interfaces Jul 2024Alzheimer's disease (AD) has a complex etiology and diverse pathological processes. The therapeutic effect of single-target drugs is limited, so simultaneous...
Alzheimer's disease (AD) has a complex etiology and diverse pathological processes. The therapeutic effect of single-target drugs is limited, so simultaneous intervention of multiple targets is gradually becoming a new research trend. Critical stages in AD progression involve amyloid-β (Aβ) self-aggregation, metal-ion-triggered fibril formation, and elevated reactive oxygen species (ROS). Herein, red blood cell membranes (RBC) are used as templates for the in situ growth of cerium oxide (CeO) nanocrystals. Then, carbon quantum dots (CQDs) are encapsulated to form nanocomposites (CQD-Ce-RBC). This strategy is combined with photothermal therapy (PTT) for AD therapy. The application of RBC enhances the materials' biocompatibility and improves immune evasion. RBC-grown CeO, the first application in the field of AD, demonstrates outstanding antioxidant properties. CQD acts as a chelating agent for copper ions, which prevents the aggregation of Aβ. In addition, the thermal effect induced by near-infrared laser-induced CQD can break down Aβ fibers and improve the permeability of the blood-brain barrier. In vivo experiments on APP/PS1 mice demonstrate that CQD-Ce-RBC combined with PTT effectively clears cerebral amyloid deposits and significantly enhances learning and cognitive abilities, thereby retarding disease progression. This innovative multipathway approach under light-induced conditions holds promise for AD treatment.
PubMed: 38954799
DOI: 10.1021/acsami.4c02088 -
Issues in Mental Health Nursing Jul 2024Electrophysiological biomarkers are being examined as potential diagnostic measures of cognitive impairment and its manifestations for psychiatric nurses' use in the... (Review)
Review
Electrophysiological biomarkers are being examined as potential diagnostic measures of cognitive impairment and its manifestations for psychiatric nurses' use in the care of Alzheimer's disease (AD). However, there is no integrative review describing the themes from the current research about electrophysiological biomarkers and the developing relationship among the themes. Characterizing this developing relationship is imperative for any possible integration of biomarkers into the care of AD by psychiatric nurses. The purpose of this integrative review is to identify themes from the current research about electrophysiological biomarkers of AD and the developing relationship among the themes, the conceivable relational premise for psychiatric nurses to integrate electrophysiological biomarkers into the screening, assessment, diagnosis, and treatment of AD for the care of persons with AD. A literature search was executed with PUBMED (accessing Medline and Elsevier) and CINAHL databases that focused on studies about electrophysiological biomarkers of AD from 2015 to 2022. Twenty-seven peer-reviewed studies met this review's inclusion criteria. Five themes emerged: (1) assessing/screening, (2) assessment differential, (3) diagnosing, (4) diagnostic accuracy, and (5) treating. These themes related sequentially and linearly, establishing a developing relationship about the risk, the onset, and the progression of AD. Electrophysiological biomarkers associated to cognitive impairment in AD, supporting the accepted understanding of the symptoms of AD. Changes in behavior and functioning were not examined, limiting the possible integration of electrophysiological biomarkers. Further investigations are warranted with an expansion of the clinical symptoms and diverse study populations.
PubMed: 38954497
DOI: 10.1080/01612840.2024.2352011 -
Natural Products and Bioprospecting Jul 2024Alzheimer's disease (AD) is a complex neurodegenerative condition. 5α-epoxyalantolactone (5α-EAL), a eudesmane-type sesquiterpene isolated from the herb of Inula...
Alzheimer's disease (AD) is a complex neurodegenerative condition. 5α-epoxyalantolactone (5α-EAL), a eudesmane-type sesquiterpene isolated from the herb of Inula macrophylla, has various pharmacological effects. This work supposed to investigate the improved impact of 5α-EAL on cognitive impairment. 5α-EAL inhibited the generation of nitric oxide (NO) in BV-2 cells stimulated with lipopolysaccharide (LPS) with an EC of 6.2 μM. 5α-EAL significantly reduced the production of prostaglandin E2 (PGE) and tumor necrosis factor-α (TNF-α), while also inhibiting the production of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proteins. The ability of 5α-EAL to penetrate the blood-brain barrier (BBB) was confirmed via a parallel artificial membrane permeation assay. Scopolamine (SCOP)-induced AD mice model was employed to assess the improved impacts of 5α-EAL on cognitive impairment in vivo. After the mice were pretreated with 5α-EAL (10 and 30 mg/kg per day, i.p.) for 21 days, the behavioral experiments indicated that the administration of the 5α-EAL could alleviate the cognitive and memory impairments. 5α-EAL significantly reduced the AChE activity in the brain of SCOP-induced AD mice. In summary, these findings highlight the beneficial effects of the natural product 5α-EAL as a potential bioactive compound for attenuating cognitive deficits in AD due to its pharmacological profile.
PubMed: 38954263
DOI: 10.1007/s13659-024-00462-y -
AAPS PharmSciTech Jul 2024Silibinin (SIL) Encapsulated Nanoliquid Crystalline (SIL-NLCs) particles were prepared to study neuroprotective effect against amyloid beta (Aβ) neurotoxicity in Balb/c...
Silibinin (SIL) Encapsulated Nanoliquid Crystalline (SIL-NLCs) particles were prepared to study neuroprotective effect against amyloid beta (Aβ) neurotoxicity in Balb/c mice model. Theses NLCs were prepared through hot emulsification and probe sonication technique. The pharmacodynamics was investigatigated on Aβ intracerebroventricular (ICV) injected Balb/c mice. The particle size, zeta potential and drug loading were optimized to be 153 ± 2.5 nm, -21 mV, and 8.2%, respectively. Small angle X-ray (SAXS) and electron microscopy revealed to crystalline shape of SIL-NLCs. Thioflavin T (ThT) fluroscence and circular dichroism (CD) technique were employed to understand monomer inhibition effect of SIL-NLCs on Aβ. In neurobehavioral studies, SIL-NLCs exhibited enhanced mitigation of memory impairment induced on by Aβ in T-maze and new object recognition test (NORT). Whereas biochemical and histopathological estimation of brain samples showed reduction in level of Aβ aggregate acetylcholine esterase (ACHE) and reactive oxygen species (ROS). SIL-NLCs treated animal group showed higher protection against Aβ toxicity compared to free SIL and Donopezil (DPZ). Therefore SIL-NLCs promises great prospect in neurodegenerative diseases such as Alzheimer's disease.
Topics: Animals; Amyloid beta-Peptides; Mice; Silybin; Mice, Inbred BALB C; Peptide Fragments; Neuroprotective Agents; Male; Brain; Particle Size; Nanoparticles; Reactive Oxygen Species; Disease Models, Animal; Alzheimer Disease; Acetylcholinesterase
PubMed: 38954224
DOI: 10.1208/s12249-024-02859-x -
European Journal of Nuclear Medicine... Jul 2024There is an unmet need for compounds to detect fibrillar forms of alpha-synuclein (αSyn) and 4-repeat tau, which are critical in many neurodegenerative diseases. Here,...
PURPOSE
There is an unmet need for compounds to detect fibrillar forms of alpha-synuclein (αSyn) and 4-repeat tau, which are critical in many neurodegenerative diseases. Here, we aim to develop an efficient surface plasmon resonance (SPR)-based assay to facilitate the characterization of small molecules that can bind these fibrils.
METHODS
SPR measurements were conducted to characterize the binding properties of fluorescent ligands/compounds toward recombinant amyloid-beta (Aβ), K18-tau, full-length 2N4R-tau and αSyn fibrils. In silico modeling was performed to examine the binding pockets of ligands on αSyn fibrils. Immunofluorescence staining of postmortem brain tissue slices from Parkinson's disease patients and mouse models was performed with fluorescence ligands and specific antibodies.
RESULTS
We optimized the protocol for the immobilization of Aβ, K18-tau, full-length 2N4R-tau and αSyn fibrils in a controlled aggregation state on SPR-sensor chips and for assessing their binding to ligands. The SPR results from the analysis of binding kinetics suggested the presence of at least two binding sites for all fibrils, including luminescent conjugated oligothiophenes, benzothiazole derivatives, nonfluorescent methylene blue and lansoprazole. In silico modeling studies for αSyn (6H6B) revealed four binding sites with a preference for one site on the surface. Immunofluorescence staining validated the detection of pS129-αSyn positivity in the brains of Parkinson's disease patients and αSyn preformed-fibril injected mice, 6E10-positive Aβ in arcAβ mice, and AT-8/AT-100-positivity in pR5 mice.
CONCLUSION
SPR measurements of small molecules binding to Aβ, K18/full-length 2N4R-tau and αSyn fibrils suggested the existence of multiple binding sites. This approach may provide efficient characterization of compounds for neurodegenerative disease-relevant proteinopathies.
PubMed: 38953933
DOI: 10.1007/s00259-024-06806-7 -
Aging Cell Jul 2024Alzheimer's disease (AD) is a neurodegenerative disorder with a distinct sex bias. Age-related vascular alterations, a hallmark of AD onset and progression, are...
Alzheimer's disease (AD) is a neurodegenerative disorder with a distinct sex bias. Age-related vascular alterations, a hallmark of AD onset and progression, are consistently associated with sexual dimorphism. Here, we conducted an integrative meta-analysis of 335,803 single-nucleus transcriptomes and 667 bulk transcriptomes from the vascular system in AD and normal aging to address the underlying sex-dependent vascular aging in AD. All vascular cell types in male AD patients exhibited an activated hypoxia response and downstream signaling pathways including angiogenesis. The female AD vasculature is characterized by increased antigen presentation and decreased angiogenesis. We further confirmed that these sex-biased alterations in the cerebral vascular emerged and were primarily determined in the early stages of AD. Sex-stratified analysis of normal vascular aging revealed that angiogenesis and various stress-response genes were downregulated concurrently with female aging. Conversely, the hypoxia response increased steadily in males upon aging. An investigation of upstream driver transcription factors (TFs) revealed that altered communication between estrogen receptor alpha (ESR1) and hypoxia induced factors during menopause contributes to the inhibition of angiogenesis during normal female vascular aging. Additionally, inhibition of CREB1, a TF that targets estrogen, is also related to female AD. Overall, our study revealed a distinct cerebral vascular profile in females and males, and revealed novel targets for precision medicine therapy for AD.
PubMed: 38953594
DOI: 10.1111/acel.14264 -
General Physiology and Biophysics Jul 2024Alzheimer's disease is currently not curable. Almost all attempts to identify disease-modifying drugs failed and the causes of disease etiology are not well understood....
Alzheimer's disease is currently not curable. Almost all attempts to identify disease-modifying drugs failed and the causes of disease etiology are not well understood. Neurofibrillary tangles composed of pathological tau protein belong to the main hallmarks of this disease. Identification of novel physiological and pathological tau interacting proteins may lead to a better understanding of Alzheimer's disease pathology and tau physiology and therefore we performed a screening of the brain library by a yeast two-hybrid system intending to identify new tau interaction partners. We identified CHORDC1 (cysteine and histidine-rich domain-containing protein 1) as a novel tau interaction partner by this approach. The CHORDC1-tau interaction was validated by co-immunoprecipitation from rat brain tissues and by in vitro co-localization in the cellular model expressing full-length human tau protein. We believe that our results can be useful for researchers studying tau protein in health and disease.
Topics: tau Proteins; Rats; Animals; Humans; Protein Binding; Brain; Protein Interaction Mapping; Two-Hybrid System Techniques
PubMed: 38953578
DOI: 10.4149/gpb_2024019