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amyloid-beta and tau protein beyond Alzheimer's disease

Neural Regeneration Research 2024年第6期19卷 1262-1276页

作者： Morteza Abyadeh Vivek Gupta Joao A.Paulo Arezoo Gohari Mahmoudabad Sina Shadfar Shahab Mirshahvaladi Veer Gupta Christine T.O.Nguyen David I.Finkelstein Yuyi You Paul A.Haynes Ghasem H.Salekdeh Stuart L.Graham Mehdi Mirzaei ProGene Technologies Pty Ltd. 2. Department of Clinical Medicine Faculty of Medicine Health and Human Sciences Macquarie Medical School Macquarie University Department of Cell Biology Harvard Medical School School of Medicine Deakin University Department of Optometry and Vision Sciences School of Health Sciences Faculty of Medicine Dentistry and Health Sciences University of Melbourne The Florey Institute of Neuroscience and Mental Health The University of Melbourne School of Natural Sciences Macquarie University

The aggregation of amyloid-beta peptide and tau protein dysregulation are implicated to play key roles in Alzheimer’s disease pathogenesis and are considered the main pathological hallmarks of this devastating disease. Physiologically, these two proteins are produced and expressed within the normal human body. However, under pathological conditions, abnormal expression, posttranslational modifications, conformational changes, and truncation can make these proteins prone to aggregation, triggering specific disease-related cascades. Recent studies have indicated associations between aberrant behavior of amyloid-beta and tau proteins and various neurological diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, as well as retinal neurodegenerative diseases like Glaucoma and age-related macular degeneration. Additionally, these proteins have been linked to cardiovascular disease, cancer, traumatic brain injury, and diabetes, which are all leading causes of morbidity and mortality. In this comprehensive review, we provide an overview of the connections between amyloid-beta and tau proteins and a spectrum of disorders.

关键词： amyloid-beta cancer cardiovascular diseases diabetes neurodegeneration Tau traumatic brain injury

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Toxicities of amyloid-beta and tau protein are reciprocally enhanced in the Drosophila model

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Neural Regeneration Research 2022年第10期17卷 2286-2292页

作者： Zhen-Dong Sun Jia-Xin Hu Jia-Rui Wu Bing Zhou Yun-Peng Huang Key Laboratory of Systems Health Science of Zhejiang Province Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhouZhejiang ProvinceChina State Key Laboratory of Membrane Biology School of Life SciencesTsinghua UniversityBeijingChina

Extracellular aggregation of amyloid-beta(Aβ)and intracellular tau tangles are two major pathogenic hallmarks and critical factors of Alzheimer’s disease.A linear interaction between Aβand tau protein has been characterized in several models.Aβinduces tau hyperphosphorylation through a complex mechanism;however,the master regulators involved in this linear process are still unclear.In our study with Drosophila melanogaster,we found that Aβregulated tau hyperphosphorylation and toxicity by activating c-Jun N-terminal kinase.Importantly,Aβtoxicity was dependent on tau hyperphosphorylation,and flies with hypophosphorylated tau were insulated against Aβ-induced toxicity.Strikingly,tau accumulation reciprocally interfered with Aβdegradation and correlated with the reduction in mRNA expression of genes encoding Aβ-degrading enzymes,including dNep1,dNep3,dMmp2,dNep4,and dIDE.Our results indicate that Aβand tau protein work synergistically to further accelerate Alzheimer’s disease progression and may be considered as a combined target for future development of Alzheimer’s disease therapeutics.

关键词： Alzheimer’s disease amyloid-beta amyloid-beta degradation Drosophila melanogaster c-Jun N-terminal kinase(JNK) neurodegeneration tau tau hyperphosphorylation

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Emerging roles of astrocytes in blood-brain barrier disruption upon amyloid-beta insults in Alzheimer's disease

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Neural Regeneration Research 2023年第9期18卷 1890-1902页

作者： Qian Yue Maggie Pui Man Hoi State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao Special Administrative RegionChina Department of Pharmaceutical Sciences Faculty of Health SciencesUniversity of MacaoMacao Special Administrative RegionChina

Blood-brain barrier disruption occurs in the early stages of Alzheimer’s disease.Recent studies indicate a link between blood-brain barrier dysfunction and cognitive decline and might accelerate Alzheimer’s disease progression.Astrocytes are the most abundant glial cells in the central nervous system with important roles in the structural and functional maintenance of the blood-brain barrier.For example,astrocytic cove rage around endothelial cells with perivascular endfeet and secretion of homeostatic soluble factors are two major underlying mechanisms of astrocytic physiological functions.Astrocyte activation is often observed in Alzheimer’s disease patients,with astrocytes expressing a high level of glial fibrillary acid protein detected around amyloid-beta plaque with the elevated phagocytic ability for amyloid-beta.Structural alte rations in Alzheimer’s disease astrocytes including swollen endfeet,somata shrinkage and possess loss contribute to disruption in vascular integrity at capillary and arte rioles levels.In addition,Alzheimer’s disease astrocytes are skewed into proinflammatory and oxidative profiles with increased secretions of vasoactive mediators inducing endothelial junction disruption and immune cell infiltration.In this review,we summarize the findings of existing literature on the relevance of astrocyte alte ration in response to amyloid pathology in the context of blood-brain barrier dysfunction.First,we briefly describe the physiological roles of astrocytes in blood-brain barrier maintenance.Then,we review the clinical evidence of astrocyte pathology in Alzheimer’s disease patients and the preclinical evidence in animal and cellular models.We further discuss the structural changes of blood-brain barrier that correlates with Alzheimer’s disease astrocyte.Finally,we evaluate the roles of soluble factors secreted by Alzheimer’s disease astrocytes,providing potential molecular mechanisms underlying blood-brain barrier modulation.We conclude with a perspective on investigating the therapeutic pot

关键词： Alzheimer’s disease amyloid-beta astrocyte(astroglial)-endothelial interaction astrocyte pathology blood-brain barrier blood-brain barrier disruption brain endothelial cell neuroinflammation reactive astrocyte

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amyloid-beta peptide and tau protein crosstalk in Alzheimer’s disease

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Neural Regeneration Research 2022年第8期17卷 1666-1674页

作者： Alejandro R.Roda Gabriel Serra-Mir Laia Montoliu-Gaya Lidia Tiessler Sandra Villegas Protein Design and Immunotherapy Group Departament de Bioquímica i Biologia MolecularFacultat de BiociènciesUniversitat Autònoma de BarcelonaBellaterraBarcelonaSpain Department of Psychiatry and Neurochemistry Institute of Neuroscience and PhysiologyThe Sahlgrenska AcademyUniversity of GothenburgSweden

Alzheimer’s disease is a neurodegenerative disease that accounts for most of the 50-million dementia cases worldwide in 2018.A large amount of evidence supports the amyloid cascade hypothesis,which states that amyloid-beta accumulation triggers tau hyperphosphorylation and aggregation in form of neurofibrillary tangles,and these aggregates lead to inflammation,synaptic impairment,neuronal loss,and thus to cognitive decline and behavioral abnormalities.The poor correlation found between cognitive decline and amyloid plaques,have led the scientific community to question whether amyloid-beta accumulation is actually triggering neurodegeneration in Alzheimer’s disease.The occurrence of tau neurofibrillary tangles better correlates to neuronal loss and clinical symptoms and,although amyloid-beta may initiate the cascade of events,tau impairment is likely the effector molecule of neurodegeneration.Recently,it has been shown that amyloid-beta and tau cooperatively work to impair transcription of genes involved in synaptic function and,more importantly,that downregulation of tau partially reverses transcriptional perturbations.Despite mounting evidence points to an interplay between amyloid-beta and tau,some factors could independently affect both pathologies.Thus,the dual pathway hypothesis,which states that there are common upstream triggers causing both amyloid-beta and tau abnormalities has been proposed.Among others,the immune system seems to be strongly involved in amyloid-beta and tau pathologies.Other factors,as the apolipoprotein Eε4 isoform has been suggested to act as a link between amyloid-beta and tau hyperphosphorylation.Interestingly,amyloid-beta-immunotherapy reduces not only amyloid-beta but also tau levels in animal models and in clinical trials.Likewise,it has been shown that tau-immunotherapy also reduces amyloid-beta levels.Thus,even though amyloid-beta immunotherapy is more advanced than tau-immunotherapy,combined amyloid-beta and tau-directed therapies at early stages of the disease have recently b

关键词： aggregation Alzheimer amyloid-beta dementia immunotherapy inflammation neurodegeneration tau

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Impaired autophagy in amyloid-beta pathology:A traditional review of recent Alzheimer's research

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The Journal of Biomedical Research 2023年第1期37卷 30-46页

作者： Minghao Yuan Yangyang Wang Zhenting Huang Feng Jing Peifeng Qiao Qian Zou Jing Li Zhiyou Cai Chongqing Medical University Chongqing 400042China Department of Neurology Chongqing General HospitalUniversity of Chinese Academy of SciencesChongqing 400013China Department of Neurology Chongqing SchoolUniversity of Chinese Academy of SciencesChongqing 400013China Chongqing Key Laboratory of Neurodegenerative Diseases Chongqing 400013China

Alzheimer’s disease(AD) is the most prevalent neurodegenerative disorder. The major pathological changes in AD progression are the generation and accumulation of amyloid-beta(Aβ) peptides as well as the presence of abnormally hyperphosphorylated tau proteins in the brain. Autophagy is a conserved degradation pathway that eliminates abnormal protein aggregates and damaged organelles. Previous studies have suggested that autophagy plays a key role in the production and clearance of Aβ peptides to maintain a steady-state of Aβ peptides levels.However, a growing body of evidence suggests that autophagy is significantly impaired in the pathogenesis of AD, especially in Aβ metabolism. Therefore, this article reviews the latest studies concerning the mechanisms of autophagy, the metabolism of Aβ peptides, and the defective autophagy in the production and clearance of Aβpeptides. Here, we also summarize the established and new strategies for targeting autophagy in vivo and through clinical AD trials to identify gaps in our knowledge and to generate further questions.

关键词： Alzheimer’s disease autophagy amyloid-beta amyloid precursor protein secretases metabolism

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Intranasal neprilysin rapidly eliminates amyloid-beta plaques, but causes plaque compensations: the explanation why the amyloid-beta cascade may fail?

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Neural Regeneration Research 2022年第9期17卷 1881-1884页

作者： Christian Humpel Laboratory of Psychiatry and Experimental Alzheimer’s Research Medical University of InnsbruckInnsbruckAustria

Neurodegenerative brain disorders are a major burden in our society,such as Alzheimer´s disease.In order to repair or prevent such diseases,drugs are designed which enter the brain,but the blood-brain barrier limits their entry and the search for alternative pathways is important.Recently,we reported that intranasal delivery of the amyloid-beta degrading enzyme neprilysin eliminated amyloid-beta plaques in transgenic Alzheimer´s disease mice.This review describes the anatomical structure of the intranasal pathway,explains the intranasal delivery of pure neprilysin,cell-loaded neprilysin(platelets)and collagen-embedded neprilysin to destruct amyloid-beta plaques in Alzheimer´s disease in transgenic APP_SweDI mice and hypothesizes why this may cause compensation and why the amyloid-beta cascade hypothesis may fail.

关键词： amyloid-beta amyloid-beta degrading enzyme clear plaque collagen biomaterial intranasal neprilysin nose-to-brain

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ImmunoPET imaging of amyloid-beta in a rat model of Alzheimer’s disease with a bispecific,brain-penetrating fusion protein

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Translational Neurodegeneration 2022年第1期11卷 70-83页

作者： Gillian Bonvicini Stina Syvänen Ken G.Andersson Merja Haaparanta-Solin Francisco López-Picón Dag Sehlin Department of Public Health and Caring Sciences Uppsala University75185 UppsalaSweden BioArctic AB 11251 StockholmSweden Preclinical Imaging Laboratory Turku PET CentreUniversity of Turku20520 TurkuFin-land MediCity Research Laboratory University of Turku20520 TurkuFinland.

Background:Hijacking the transferrin receptor(TfR)is an effective strategy to transport amyloid-beta(Aβ)immuno-positron emission tomography(immunoPET)ligands across the blood-brain barrier(BBB).Such ligands are more sensitive and specific than small-molecule ligands at detecting Aβpathology in mouse models of Alzheimer’s disease(AD).This study aimed to determine if this strategy would be as sensitive in rats and to assess how TfR affinity affects BBB transport of bispecific immunoPET radioligands.Methods:Two affinity variants of the rat TfR antibody,OX26,were chemically conjugated to a F(ab′)2 fragment of the anti-Aβantibody,bapineuzumab(Bapi),to generate two bispecific fusion proteins:OX265-F(ab′)2-Bapi and OX2676-F(ab′)2-Bapi.Pharmacokinetic analyses were performed 4 h and 70 h post-injection of radioiodinated fusion proteins in wild-type(WT)rats.[124I]I-OX265-F(ab′)2-Bapi was administered to TgF344-AD and WT rats for in vivo PET imaging.Ex vivo distribution of injected[124I]I-OX265-F(ab′)2-Bapi and Aβpathology were assessed.Results:More[125I]I-OX265-F(ab′)2-Bapi was taken up into the brain 4 h post-administration than[124I]I-OX2676-F(ab′)2-Bapi.[124I]I-OX265-F(ab′)2-Bapi PET visualized Aβpathology with significantly higher signals in the TgF344-AD rats than in the WT littermates without Aβpathology.The PET signals significantly correlated with Aβlevels in AD animals.Conclusion:Affinity to TfR affects how efficiently a TfR-targeting bispecific fusion protein will cross the BBB,such that the higher-affinity bispecific fusion protein crossed the BBB more efficiently.Furthermore,bispecific immunoPET imaging of brain Aβpathology using TfR-mediated transport provides good imaging contrast between TgF344-AD and WT rats,suggesting that this immunoPET strategy has the potential to be translated to higher species.

关键词： ImmunoPET Transferrin receptor Alzheimer’s disease amyloid-beta

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Liver as a new target organ in Alzheimer's disease:insight from cholesterol metabolism and its role in amyloid-beta clearance

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Neural Regeneration Research 2025年第3期20卷 695-714页

作者： Beibei Wu Yuqing Liu Hongli Li Lemei Zhu Lingfeng Zeng Zhen Zhang Weijun Peng Department of Integrated Traditional Chinese&Western Medicine The Second Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina Academician Workstation Changsha Medical UniversityChangshaHunan ProvinceChina Yangsheng College of Traditional Chinese Medicine Guizhou University of Traditional Chinese MedicineGuiyangGuizhou ProvinceChina Qinhuangdao Shanhaiguan Pharmaceutical Co. LtdQinhuangdaoHebei ProvinceChina National Clinical Research Center for Mental Disorder The Second Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina

Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.

关键词： ABCA1 Alzheimer's disease amyloid-beta apolipoprotein E cholesterol metabolism liver liver X receptor low-density lipoprotein receptor-related protein 1 peripheral clearance tauroursodeoxycholic acid

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Detection of amyloid-beta by Fmoc-KLVFF self-assembled fluorescent nanoparticles for Alzheimer’s disease diagnosis

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Chinese Chemical Letters 2021年第3期32卷 1066-1070页

作者： Dingchang Liu Dongjie Fu Lianbing Zhang Leming Sun School of Life Sciences Key Laboratory of Space Bioscience&BiotechnologyNorthwestern Polytechnical UniversityXi’an 710072China

The abnormal aggregation of amyloid-beta(Aβ)has been widely believed to play an important role in the pathogenesis of Alz heimer’s disease(AD),which is also recognized as one of the main biomarkers for AD diagnosis.The peptide sequence Lys-Leu-Val-Phe-Phe(KLVFF)is considered as the main driver of the fibrillation of Aβ,which also can be utilized to target Aβand inhibit its aggregation.In this study,KLVFF and Fmoc-KLVFF fluorescent nanoparticles were self-assembled through zinc coordination andπ-πstacking.The recognition of Aβaggregates including oligomers and fibrils by fluorescent nanoparticles can be realized through aromatic,hydrophobic,and hydrogen-bond interactions.The fluorescent nanoprobes can distinguish Aβaggregation formats and detect Aβat the limit of 1 pg/mL(S/N=3).Hence,the detection of Aβaggregates by fluorescent peptide nanoparticles has great potential for AD diagnosis and progression prediction.

关键词： Self-assembly Fmoc-KLVFF Fluorescent nanoparticles amyloid-beta Alzheimer’s disease Diagnosis

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Cyanidin suppresses amyloid beta-induced neurotoxicity by inhibiting reactive oxygen speciesmediated DNA damage and apoptosis in PC12 cells

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Neural Regeneration Research 2016年第5期11卷 795-800页

作者： Yi Wang Xiao-ting Fu Da-wei Li Kun Wang Xin-zhi Wang Yuan Li Bao-liang Sun Xiao-yi Yang Zun-cheng Zheng Nam Chun Cho Department of Ophthalmology Chonbuk National University Medical College Key Lab of Cerebral Microcirculation in Universities of Shandong Taishan Medical University Department of Rehabilitation Taian Central Hospital

amyloid beta（Aβ）-induced oxidative stress is a major pathologic hallmark of Alzheimer＇s disease. Cyanidin, a natural flavonoid compound, is neuroprotective against oxidative damage-mediated degeneration. However, its molecular mechanism remains unclear. Here, we investigated the effects of cyanidin pretreatment against Aβ-induced neurotoxicity in PC12 cells, and explored the underlying mechanisms. Cyanidin pretreatment significantly attenuated Aβ-induced cell mortality and morphological changes in PC12 cells. Mechanistically, cyanidin effectively blocked apoptosis induced by Aβ, by restoring the mitochondrial membrane potential via upregulation of Bcl-2 protein expression. Moreover, cyanidin markedly protected PC12 cells from Aβ-induced DNA damage by blocking reactive oxide species and superoxide accumulation. These results provide evidence that cyanidin suppresses Aβ-induced cytotoxicity, by preventing oxidative damage mediated by reactive oxide species, which in turn inhibits mitochondrial apoptosis. Our study demonstrates the therapeutic potential of cyanidin in the prevention of oxidative stress-mediated Aβ neurotoxicity.

关键词： nerve regeneration cyanidin amyloid-beta oxidative damage reactive oxide species apoptosis neural regeneration

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