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Multidimensional autophagy nano-regulator boosts alzheimer's disease treatment by improving both extra/intraneuronal homeostasis

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Acta Pharmaceutica sinica B 2024年第3期14卷 1380-1399页

作者： Yixian Li Peng Yang Ran Meng shuting Xu Lingling Zhou Kang Qian Pengzhen Wang Yunlong Cheng Dongyu sheng Minjun Xu Tianying Wang Jing Wu Jinxu Cao Qizhi Zhang Key Laboratory of smart Drug Delivery Ministry of EducationSchool of PharmacyFudan UniversityShanghai 201203China

Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in alzheimer’s disease(AD)collectively culminate in neuronal deterioration.In the context of AD,autophagy dysfunction,a multi-link obstacle involving autophagy downregulation and lysosome defects in neurons/microglia is highly implicated in intra/extraneuronal pathological processes.Therefore,multidimensional autophagy regulation strategies co-manipulating“autophagy induction”and“lysosome degradation”in dual targets(neuron and microglia)are more reliable for AD treatment.Accordingly,we designed an RP-1 peptide-modified reactive oxygen species(ROs)-responsive micelles(RT-NM)loading rapamycin or gypenoside XVII.Guided by RP-1 peptide,the ligand of receptor for advanced glycation end products(RAGE),RT-NM efficiently targeted neurons and microglia in AD-affected region.This nanocombination therapy activated the whole autophagy-lysosome pathway by autophagy induction(rapamycin)and lysosome improvement(gypenoside XVII),thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes,and promoting Aβ phagocytosis.Resultantly,it decreased aberrant protein burden,alleviated neuroinflammation,and eventually ameliorated memory defects in 3×Tg-AD transgenic mice.Our research developed a multidimensional autophagy nano-regulator to boost the efficacy of autophagy-centered AD therapy.

关键词： Autophagy-lysosome pathway alzheimer’s disease Proteostasis Neuroinflammation Multi-target therapy Rapamycin Gypenoside XVII Cascade dual-targeting

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Rebuilding insight into the pathophysiology of alzheimer’s disease through new blood-brain barrier models

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Neural Regeneration Research 2024年第9期19卷 1954-1960页

作者： Kinya Matsuo Hideaki Nshihara Yamaguchi University Graduate school of Medicine YamaguchiJapan Department of Neurotherapeutics Yamaguchi UniversityUbeJapan

The blood-brain barrier is a unique function of the microvasculature in the brain parenchyma that maintains homeostasis in the central nervous system.Blood-brain barrier breakdown is a common pathology in various neurological diseases,such as alzheimer’s disease,stroke,multiple sclerosis,and Parkinson’s disease.Traditionally,it has been considered a consequence of neuroinflammation or neurodegeneration,but recent advanced imaging techniques and detailed studies in animal models show that blood-brain barrier breakdown occurs early in the disease process and may precede neuronal loss.Thus,the blood-brain barrier is attractive as a potential therapeutic target for neurological diseases that lack effective therapeutics.To elucidate the molecular mechanism underlying blood-brain barrier breakdown and translate them into therapeutic strategies for neurological diseases,there is a growing demand for experimental models of human origin that allow for functional assessments.Recently,several human induced pluripotent stem cell-derived blood-brain barrier models have been established and various in vitro blood-brain barrier models using microdevices have been proposed.Especially in the alzheimer’s disease field,the human evidence for blood-brain barrier dysfunction has been demonstrated and human induced pluripotent stem cell-derived blood-brain barrier models have suggested the putative molecular mechanisms of pathological blood-brain barrier.In this review,we summarize recent evidence of blood-brain barrier dysfunction in alzheimer’s disease from pathological analyses,imaging studies,animal models,and stem cell sources.Additionally,we discuss the potential future directions for blood-brain barrier research.

关键词： alzheimer’s disease blood-brain barrier human induced pluripotent stem cells

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Neural stem cell-derived exosomes promote mitochondrial biogenesis and restore abnormal protein distribution in a mouse model of alzheimer's disease

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Neural Regeneration Research 2024年第7期19卷 1593-1601页

作者： Bo Li Yujie Chen Yan Zhou Xuanran Feng Guojun Gu shuang Han Nianhao Cheng Yawen sun Yiming Zhang Jiahui Cheng Qi Zhang Wei Zhang Jianhui Liu Department of Radiology Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina Morphology and spatial Multi-Omics Technology Platform Shanghai Institute of Nutrition and HealthChinese Academy of SciencesShanghaiChina Department of Anesthesiology Tongji HospitalSchool of MedicineTongji UniversityShanghaiChina Department of Blood Transfusion Huashan HospitalFudan UniversityShanghaiChina

Mitochondrial dysfunction is a hallmark of alzheimer’s disease.We previously showed that neural stem cell-derived extracellular vesicles improved mitochondrial function in the cortex of AP P/Ps1 mice.Because alzheimer’s disease affects the entire brain,further research is needed to elucidate alterations in mitochondrial metabolism in the brain as a whole.Here,we investigated the expression of several important mitochondrial biogenesis-related cytokines in multiple brain regions after treatment with neural stem cell-derived exosomes and used a combination of whole brain clearing,immunostaining,and lightsheet imaging to clarify their spatial distribution.Additionally,to clarify whether the sirtuin 1(sIRT1)-related pathway plays a regulatory role in neural stem cell-de rived exosomes interfering with mitochondrial functional changes,we generated a novel nervous system-sIRT1 conditional knoc kout AP P/Ps1mouse model.Our findings demonstrate that neural stem cell-de rived exosomes significantly increase sIRT1 levels,enhance the production of mitochondrial biogenesis-related fa ctors,and inhibit astrocyte activation,but do not suppress amyloid-βproduction.Thus,neural stem cell-derived exosomes may be a useful therapeutic strategy for alzheimer’s disease that activates the sIRT1-PGC1αsignaling pathway and increases NRF1 and COXIV synthesis to improve mitochondrial biogenesis.In addition,we showed that the spatial distribution of mitochondrial biogenesis-related factors is disrupted in alzheimer’s disease,and that neural stem cell-derived exosome treatment can reverse this effect,indicating that neural stem cell-derived exosomes promote mitochondrial biogenesis.

关键词： alzheimer’s disease mitochondrial biogenesis neural stem cell-derived exosome sIRT1-PGC1α regional brain distribution whole brain clearing and imaging

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Neural stem cells promote neuroplasticity: a promising therapeutic strategy for the treatment of alzheimer’s disease

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Neural Regeneration Research 2024年第3期19卷 619-628页

作者： Jun Chang Yujiao Li Xiaoqian shan Xi Chen Xuhe Yan Jianwei Liu Lan Zhao First Teaching Hospital of Tianjin University of Traditional Chinese Medicine TianjinChina National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion TianjinChina Tianjin University of Traditional Chinese Medicine TianjinChina

Recent studies have demonstrated that neuroplasticity,such as synaptic plasticity and neurogenesis,exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with alzheimer’s disease.Hence,promoting neuroplasticity may represent an effective strategy with which alzheimer’s disease can be alleviated.Due to their significant ability to self-renew,differentiate,and migrate,neural stem cells play an essential role in reversing synaptic and neuronal damage,reducing the pathology of alzheimer’s disease,including amyloid-β,tau protein,and neuroinflammation,and secreting neurotrophic factors and growth factors that are related to plasticity.These events can promote synaptic plasticity and neurogenesis to repair the microenvironment of the mammalian brain.Consequently,neural stem cells are considered to represent a potential regenerative therapy with which to improve alzheimer’s disease and other neurodegenerative diseases.In this review,we discuss how neural stem cells regulate neuroplasticity and optimize their effects to enhance their potential for treating alzheimer’s disease in the clinic.

关键词： alzheimer’s disease amyloid-β cell therapy extracellular vesicle neural stem cell synaptic plasticity tau

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Targeting tau in alzheimer's disease:from mechanisms to clinical therapy

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Neural Regeneration Research 2024年第7期19卷 1489-1498页

作者： Jinwang Ye Huali Wan sihua Chen Gong-Ping Liu shenzhen Key Laboratory of Marine Biotechnology and Ecology College of Life Sciences and OceanographyShenzhen UniversityShenzhenGuangdong ProvinceChina Department of Laboratory Medicine Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouGuangdong ProvinceChina Co-innovation Center of Neurodegeneration Nantong UniversityNantongJiangsu ProvinceChina Department of Pathophysiology School of Basic Medicine and the Collaborative Innovation Center for Brain ScienceKey Laboratory of Ministry of Education of China and Hubei Province for Neurological DisordersTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei ProvinceChina

alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neurofibrillary tangles,fo rmed by tau protein,in the cells.While there are amyloid-β-ta rgeting therapies for the treatment of alzheimer’s disease,these therapies are costly and exhibit potential negative side effects.Mounting evidence suggests significant involvement of tau protein in alzheimer’s disease-related neurodegeneration.As an important microtubule-associated protein,tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth.In fact,clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-βin the brain.Various therapeutic strategies targeting tau protein have begun to emerge,and are considered possible methods to prevent and treat alzheimer’s disease.specifically,abnormalities in post-translational modifications of the tau protein,including aberrant phosphorylation,ubiquitination,small ubiquitin-like modifier(sUMO)ylation,acetylation,and truncation,contribute to its microtubule dissociation,misfolding,and subcellular missorting.This causes mitochondrial damage,synaptic impairments,gliosis,and neuroinflammation,eventually leading to neurodegeneration and cognitive deficits.This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of alzheimer’s disease and discusses tau-targeted treatment of alzheimer’s disease.

关键词： acetylation alzheimer’s disease cognitive deficits gliosis mitochondria damage neuroinflammation phosphorylation synaptic impairments tau tau immunotherapy

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Ferroptosis mechanism and alzheimer's disease

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Neural Regeneration Research 2024年第8期19卷 1741-1750页

作者： Lina Feng Jingyi sun Ling Xia Qiang shi Yajun Hou Lili Zhang Mingquan Li Cundong Fan Baoliang sun shandong Key Laboratory of TCM Multi-Target Intervention and disease Control the Second Affiliated Hospital of Shandong First Medical UniversityTaianShandong ProvinceChina Department of Internal Medicine Taian Traffic HospitalTaianShandong ProvinceChina Department of Neurology the Third Affiliated Clinical Hospital of Changchun University of Chinese MedicineChangchunJilin ProvinceChina

Regulated cell death is a genetically determined form of programmed cell death that commonly occurs during the development of living organisms.This process plays a crucial role in modulating homeostasis and is evolutionarily conserved across a diverse range of living organisms.Ferroptosis is a classic regulatory mode of cell death.Extensive studies of regulatory cell death in alzheimer’s disease have yielded increasing evidence that fe rroptosis is closely related to the occurrence,development,and prognosis of alzheimer’s disease.This review summarizes the molecular mechanisms of ferroptosis and recent research advances in the role of ferro ptosis in alzheimer’s disease.Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for alzheimer’s disease.

关键词： alzheimer’s disease apolipoprotein E Fe^(2+) ferroptosis glial cell glutathione peroxidase 4 imbalance in iron homeostasis lipid peroxidation regulated cell death system Xc^(-)

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Circadian rhythm disruption and retinal dysfunction:a bidirectional link in alzheimer’s disease?

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Neural Regeneration Research 2024年第9期19卷 1967-1972页

作者： Laura Carrero DesireéAntequera Cristina Municio Eva Carro Group of Neurodegenerative diseases Hospital Universitario 12 de Octubre Research Institute(imas12)MadridSpainNetwork Center for Biomedical Research in Neurodegenerative Diseases(CIBERNED)ISCIIIMadridSpain PhD Program in Neuroscience Autonoma de Madrid UniversityMadridSpain Neurobiology of alzheimer’s disease Unit Functional Unit for Research into Chronic DiseasesInstituto de Salud Carlos IIIMadridSpainNetwork Centre for Biomedical Research in Neurodegenerative Diseases(CIBERNED)ISCIIIMadridSpain

Dysfunction in circadian rhythms is a common occurrence in patients with alzheimer’s disease.A predominant function of the retina is circadian synchronization,carrying information to the brain through the retinohypothalamic tract,which projects to the suprachiasmatic nucleus.Notably,alzheimer’s disease hallmarks,including amyloid-β,are present in the retinas of alzheimer’s disease patients,followed/associated by structural and functional disturbances.However,the mechanistic link between circadian dysfunction and the pathological changes affecting the retina in alzheimer’s disease is not fully understood,although some studies point to the possibility that retinal dysfunction could be considered an early pathological process that directly modulates the circadian rhythm.

关键词： alzheimer’s disease amyloid circadian rhythm neurodegeneration retina

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Interplay between microglia and environmental risk factors in alzheimer's disease

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Neural Regeneration Research 2024年第8期19卷 1718-1727页

作者： Miaoping Zhang Chunmei Liang Xiongjin Chen Yujie Cai Lili Cui Guangdong Key Laboratory of Age-Related Cardiac and Cerebral diseases Affiliated Hospital of Guangdong Medical UniversityZhanjiangGuangdong ProvinceChina

alzheimer s disease,among the most common neurodegenerative disorders,is chara cterized by progressive cognitive impairment.At present,the alzheimer’s disease main risk remains genetic ris ks,but major environmental fa ctors are increasingly shown to impact alzheimer’s disease development and progression.Microglia,the most important brain immune cells,play a central role in alzheimer’s disease pathogenesis and are considered environmental and lifestyle"sensors."Factors like environmental pollution and modern lifestyles(e.g.,chronic stress,poor dietary habits,sleep,and circadian rhythm disorde rs)can cause neuroinflammato ry responses that lead to cognitive impairment via microglial functioning and phenotypic regulation.However,the specific mechanisms underlying interactions among these facto rs and microglia in alzheimer’s disease are unclear.Herein,we:discuss the biological effects of air pollution,chronic stress,gut micro biota,sleep patterns,physical exercise,cigarette smoking,and caffeine consumption on microglia;consider how unhealthy lifestyle factors influence individual susceptibility to alzheimer’s disease;and present the neuroprotective effects of a healthy lifestyle.Toward intervening and controlling these environmental risk fa ctors at an early alzheimer’s disease stage,understanding the role of microglia in alzheimer’s disease development,and to rgeting strategies to to rget microglia,co uld be essential to future alzheimer’s disease treatments.

关键词： alzheimer’s disease chronic stress environmental factor gut microbiota microglia particulate matter with diameter<2.5μm

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Intermittent Theta Burst stimulation Attenuates Cognitive Deficits and alzheimer’s disease-Type Pathologies via IsCA1-Mediated Mitochondrial Modulation in APP/Ps1 Mice

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Neuroscience Bulletin 2024年第2期40卷 182-200页

作者： Yang Zhu Hao Huang Zhi Chen Yong Tao Ling-Yi Liao shi-Hao Gao Yan-Jiang Wang Chang-Yue Gao Department of Rehabilitation Medicine Daping HospitalArmy Medical UniversityChongqing 400042China Department of Neurology and Center for Clinical Neuroscience Daping HospitalArmy Medical UniversityChongqing 400042China Department of special Medicine Daping HospitalArmy Medical UniversityChongqing 400042China

Intermittent theta burst stimulation(iTBs),a time-saving and cost-effective repetitive transcranial magnetic stimulation regime,has been shown to improve cognition in patients with alzheimer’s disease(AD).However,the specific mechanism underlying iTBs-induced cognitive enhancement remains unknown.Previous studies suggested that mitochondrial functions are modulated by magnetic stimulation.Here,we showed that iTBs upregulates the expression of iron-sulfur cluster assembly 1(IsCA1,an essential regulatory factor for mitochondrial respiration)in the brain of APP/Ps1 mice.In vivo and in vitro studies revealed that iTBs modulates mitochondrial iron-sulfur cluster assembly to facilitate mitochondrial respiration and function,which is required for IsCA1.Moreover,iTBs rescues cognitive decline and attenuates AD-type pathologies in APP/Ps1 mice.The present study uncovers a novel mechanism by which iTBs modulates mitochondrial respiration and function via IsCA1-mediated iron-sulfur cluster assembly to alleviate cognitive impairments and pathologies in AD.We provide the mechanistic target of iTBs that warrants its therapeutic potential for AD patients.

关键词： Intermittent theta burst stimulation alzheimer’s disease Iron-sulfur cluster assembly 1 Mitochondrial dysfunction Neurodegeneration

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Tau truncation in the pathogenesis of alzheimer's disease: a narrative review

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Neural Regeneration Research 2024年第6期19卷 1221-1232页

作者： Dandan Chu Xingyue Yang Jing Wang Yan Zhou Jin-Hua Gu Jin Miao Feng Wu Fei Liu Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products Coinnovation Center of Neuroregeneration Nantong University 2. Department of Pharmacology School of Pharmacy Nantong University 3. Department of Biochemistry and Molecular Biology School of Medicine Nantong University 4. Department of Clinical Pharmacy Affiliated Maternity and Child Health Care Hospital of Nantong University Nantong University 5. Laboratory of Animal Center Nantong University Department of Neurochemistry Inge Grundke-Iqbal Research Floor New York State Institute for Basic Research in Developmental Disabilities

alzheimer’s disease is characterized by two major neuropathological hallmarks—the extracellular β-amyloid plaques and intracellular neurofibrillary tangles consisting of aggregated and hyperphosphorylated Tau protein. Recent studies suggest that dysregulation of the microtubuleassociated protein Tau, especially specific proteolysis, could be a driving force for alzheimer’s disease neurodegeneration. Tau physiologically promotes the assembly and stabilization of microtubules, whereas specific truncated fragments are sufficient to induce abnormal hyperphosphorylation and aggregate into toxic oligomers, resulting in them gaining prion-like characteristics. In addition, Tau truncations cause extensive impairments to neural and glial cell functions and animal cognition and behavior in a fragment-dependent manner. This review summarizes over 60 proteolytic cleavage sites and their corresponding truncated fragments, investigates the role of specific truncations in physiological and pathological states of alzheimer’s disease, and summarizes the latest applications of strategies targeting Tau fragments in the diagnosis and treatment of alzheimer’s disease.

关键词： alzheimer’s disease cleavage site diagnosis marker neurofibrillary tangles phosphorylation Tau Tau aggregation therapy truncation

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