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significance of native PLGA nanoparticles in the treatment of Alzheimer’s disease pathology

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Bioactive Materials 2022年第11期7卷 506-525页

作者： Bibin Anand Qi Wu Maryam Nakhaei-Nejad Govindarajan Karthivashan Lyudmyla Dorosh sara Amidian Abhishek Dahal Xiuju Li Maria stepanova Holger Wille Fabrizio Giuliani satyabrata Kar Department of Medicine(Neurology) University of AlbertaEdmontonAlbertaT6G 2M8Canada Centre for Prions and Protein Folding diseases University of AlbertaEdmontonAlbertaT6G 2M8Canada Department of Electrical and Computer Engineering University of AlbertaEdmontonAlbertaT6G 2M8Canada Department of Biochemistry University of AlbertaEdmontonAlbertaT6G 2M8Canada Neuroscience and Mental Health Institute University of AlbertaEdmontonAlbertaT6G 2M8Canada

Alzheimer’s disease (AD) is believed to be triggered by increased levels/aggregation of β-amyloid (Aβ) peptides. At present, there is no effective disease-modifying treatment for AD. Here, we evaluated the therapeutic potential of FDA-approved native poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles on Aβ aggregation and in cellular/ animal models of AD. Our results showed that native PLGA can not only suppress the spontaneous aggregation but can also trigger disassembly of preformed Aβ aggregates. spectroscopic studies, molecular dynamics simu-lations and biochemical analyses revealed that PLGA, by interacting with the hydrophobic domain of Aβ1-42, prevents a conformational shift towards the β-sheet structure, thus precluding the formation and/or triggering disassembly of Aβ aggregates. PLGA-treated Aβ samples can enhance neuronal viability by reducing phosphor-ylation of tau protein and its associated signaling mechanisms. Administration of PLGA can interact with Aβ aggregates and attenuate memory deficits as well as Aβ levels/deposits in the 5xFAD mouse model of AD. PLGA can also protect iPsC-derived neurons from AD patients against Aβ toxicity by decreasing tau phosphorylation. These findings provide unambiguous evidence that native PLGA, by targeting different facets of the Aβ axis, can have beneficial effects in mouse neurons/animal models as well as on iPsC-derived AD neurons - thus signifying its unique therapeutic potential in the treatment of AD pathology.

关键词： Alzheimer’s disease β-amyloid Nanoparticles Neuroprotection Peptide aggregation

Pharmacological modulation of autophagy for alzheimer's disease therapy:Opportunities and obstacles

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Acta Pharmaceutica sinica B 2022年第4期12卷 1688-1706页

作者： Zhiqiang Deng Yu Dong Xiaoting Zhou Jia-Hong Lu Zhenyu Yue state Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao SAR 999078China Department of Neurology the Friedman Brain InstituteIcahn School of Medicine at Mount SinaiNew YorkNY 10029USA Department of Geriatrics Xiangya HospitalCentral South UniversityChangsha 410008China

alzheimer's disease(AD)is a prevalent and deleterious neurodegenerative disorder characterized by an irreversible and progressive impairment of cognitive abilities as well as the formation of amyloidβ(Aβ)plaques and neurofibrillary tangles(NFTs)in the brain.By far,the precise mechanisms of AD are not fully understood and no interventions are available to effectively slow down progression of the disease.Autophagy is a conserved degradation pathway that is crucial to maintain cellular homeostasis by targeting damaged organelles,pathogens,and disease-prone protein aggregates to lysosome for degradation.Emerging evidence suggests dysfunctional autophagy clearance pathway as a potential cellular mechanism underlying the pathogenesis of AD in affected neurons.Here we summarize the current evidence for autophagy dysfunction in the pathophysiology of AD and discuss the role of autophagy in the regulation of AD-related protein degradation and neuroinflammation in neurons and glial cells.Finally,we review the autophagy modulators reported in the treatment of AD models and discuss the obstacles and opportunities for potential clinical application of the novel autophagy activators for AD therapy.

关键词： Alzheimer’s disease Autophagy Autophagy modulators Genetic modulation Neuronal autophagy Microglial autophagy LC3-associated phagocytosis Neuroinflammation

Unfolded p53 in non-neuronal cells supports bacterial etiology of Alzheimer’s disease

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Neural Regeneration Research 2022年第12期17卷 2619-2622页

作者： Peter W.French Innlanz Limited SydneyNSWAustralia

Alzheimer’s disease has proven to be largely intractable to treatment,despite years of research,and numerous trials of therapies that target the hallmarks of the disease-amyloid plaques and neurofibrillary tangles.The etiology of Alzheimer’s disease remains elusive.There is a growing body of evidence for an infectious trigger of Alzheimer’s disease,and,in particular,the focus has been on the oral pathogen Porphyromonas gingivalis(P.gingivalis).Reports of the expression of a misfolded form of p53 in non-neuronal cells(fibroblasts,peripheral blood mononuclear cells,and B cells)and serum,which appears several years before clinical symptoms manifest,may provide further support for the role of bacteria in general,and P.gingivalis in particular,in the initiation of the disease.This review presents a model of the pathway from initial oral infection with P.gingivalis to amyloid plaque formation and neuronal degeneration,via the steps of chronic periodontitis;secretion of the inflammagens lipopolysaccharide and gingipains into the bloodstream;induction of an inflammatory response in both peripheral cells and tissues;disruption of the blood-brain barrier,and entry into the central nervous system of the inflammagens and the P.gingivalis bacteria themselves.In this model,the misfolded p53(or“unfolded p53”;up53)is induced in non-neuronal cells and upregulated in serum as a result of oxidative stress due to lipopolysaccharide from P.gingivalis.up53 is therefore a potential biomarker for early diagnosis of the presence of a causative agent of Alzheimer’s disease.Fastidious dental hygiene and aggressive antibiotic treatment may prevent the patient progressing to clinical Alzheimer’s disease if serum up53 is detected at this pre-symptomatic stage.

关键词： Alzheimer’s disease gingipains lipopolysaccharide P.gingivalis periodontitis unfolded p53

APOE ε4-dependent effects on the early amyloid pathology in induced neurons of patients with Alzheimer’s disease

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Translational Neurodegeneration 2022年第1期11卷 248-261页

作者： Hongwon Kim siyoung Kim Byounggook Cho Jaein shin Jongpil Kim Department of Biomedical Engineering Dongguk UniversityPildong-ro 1-gil 30Jung-GuSeoul 04620Republic of Korea Laboratory of stem Cells&Gene Editing Department of ChemistryDongguk UniversityPildong-ro 1-gil 30Jung-GuSeoul 04620Republic of Korea.

Background: The ε4 allele of apolipoprotein E (APOE ε4) is the strongest known genetic risk factor for late-onset Alzheimer’s disease (AD), associated with amyloid pathogenesis. However, it is not clear how APOE ε4 accelerates amyloid-beta (Aβ) deposition during the seeding stage of amyloid development in AD patient neurons. Methods: AD patient induced neurons (iNs) with an APOE ε4 inducible system were prepared from skin fibroblasts of AD patients. Transcriptome analysis was performed using RNA isolated from the AD patient iNs expressing APOE ε4 at amyloid-seeding and amyloid-aggregation stages. Knockdown of IGFBP3 was applied in the iNs to investigate the role of IGFBP3 in the APOE ε4-mediated amyloidosis. Results: We optimized amyloid seeding stage in the iNs of AD patients that transiently expressed APOE ε4. Remarka-bly, we demonstrated that Aβ pathology was aggravated by the induction of APOE ε4 gene expression at the amyloid early-seeding stage in the iNs of AD patients. Moreover, transcriptome analysis in the early-seeding stage revealed that IGFBP3 was functionally important in the molecular pathology of APOE ε4-associated AD. Conclusions: Our findings suggest that the presence of APOE ε4 at the early Aβ-seeding stage in patient iNs is critical for aggravation of sporadic AD pathology. These results provide insights into the importance of APOE ε4 expression for the progression and pathogenesis of sporadic AD.

关键词： Alzheimer’s disease Direct conversion Apolipoprotein E Induced neuron Amyloid Presenilin

Diagnosis and Detection of Alzheimer’s disease Using Learning Algorithm

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Big Data Mining and Analytics 2023年第4期6卷 504-512页

作者： Gargi Pant shukla santosh Kumar saroj Kumar Pandey Rohit Agarwal Neeraj Varshney Ankit Kumar the Department of Management Doon Business SchoolDehradun 248001India. Jaipuria Institute of Management Jaipur 302033India Department of Computer Engineering and Apllications GLA UniversityMathura 281406India.

In Computer-Aided Detection(CAD)brain disease classification is a vital issue.Alzheimer’s disease(AD)and brain tumors are the primary reasons of death.The studies of these diseases are carried out by Magnetic Resonance Imaging(MRI),Positron Emission Tomography(PET),and Computed Tomography(CT)scans which require expertise to understand the modality.The disease is the most prevalent in the elderly and can be fatal in its later stages.The result can be determined by calculating the mini-mental state exam score,following which the MRI scan of the brain is successful.Apart from that,various classification algorithms,such as machine learning and deep learning,are useful for diagnosing MRI scans.However,they do have some limitations in terms of accuracy.This paper proposes some insightful pre-processing methods that significantly improve the classification performance of these MRI images.Additionally,it reduced the time it took to train the model of various pre-existing learning algorithms.A dataset was obtained from Alzheimer’s disease Neurological Initiative(ADNI)and converted from a 4D format to a 2D format.selective clipping,grayscale image conversion,and histogram equalization techniques were used to pre-process the images.After pre-processing,we proposed three learning algorithms for AD classification,that is random forest,XGBoost,and Convolution Neural Networks(CNN).Results are computed on dataset and show that it outperformed with exiting work in terms of accuracy is 97.57%and sensitivity is 97.60%.

关键词： Alzheimer’s disease deep learning random forest XGBoost

A review of brain imaging biomarker genomics in Alzheimer’s disease:implementation and perspectives

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Translational Neurodegeneration 2022年第1期11卷 294-330页

作者： Lanlan Li Xianfeng Yu Can sheng Xueyan Jiang Qi Zhang Ying Han Jiehui Jiang school of Information and Communication Engineering Shanghai UniversityShanghai 200444China school of Biomedical Engineering Hainan UniversityHaikou 570228China Department of Neurology Xuanwu Hospital of Capital Medical UniversityBeijing 100053China Institute of Biomedical Engineering School of Life ScienceShanghai UniversityShanghai 200444China.

Alzheimer’s disease(AD)is a progressive neurodegenerative disease with phenotypic changes closely associated with both genetic variants and imaging pathology.Brain imaging biomarker genomics has been developed in recent years to reveal potential AD pathological mechanisms and provide early diagnoses.This technique integrates multimodal imaging phenotypes with genetic data in a noninvasive and high-throughput manner.In this review,we summarize the basic analytical framework of brain imaging biomarker genomics and elucidate two main implementation scenarios of this technique in AD studies:(1)exploring novel biomarkers and seeking mutual interpretability and(2)providing a diagnosis and prognosis for AD with combined use of machine learning methods and brain imaging biomarker genomics.Importantly,we highlight the necessity of brain imaging biomarker genomics,discuss the strengths and limitations of current methods,and propose directions for development of this research field.

关键词： Imaging biomarker genomics Alzheimer’s disease Evolving technologies Implementation

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

The COVID-19 pandemic and Alzheimer’s disease: mutual risks and mechanisms

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Translational Neurodegeneration 2022年第1期11卷 343-360页

作者： Feng Chen Yanting Chen Yongxiang Wang Qiongwei Ke Lili Cui Guangdong Key Laboratory of Age-Related Cardiac and Cerebral diseases Department of NeurologyAffiliated Hospital of Guangdong Medical Univer-sityZhanjiangChina Key Laboratory of Animal Models and Human disease Mechanisms of the Chinese Academy of sciences&Yunnan Province Kunming Institute of Zoology Chinese Academy of sciences KunmingYunnanChina.

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (sARs- CoV-2), is a life-threatening disease, especially in elderly individuals and those with comorbidities. The predominant clinical manifestation of COVID-19 is respiratory dysfunction, while neurological presentations are increasingly being recognized. sARs-CoV-2 invades host cells primarily via attachment of the spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor expressed on cell membranes. Patients with Alzheimer’s disease (AD) are more susceptible to sARs-CoV-2 infection and prone to severe clinical outcomes. Recent studies have revealed some common risk fac-tors for AD and COVID-19. An understanding of the association between COVID-19 and AD and the potential related mechanisms may lead to the development of novel approaches to treating both diseases. In the present review, we first summarize the mechanisms by which sARs-CoV-2 invades the central nervous system (CNs) and then discuss the associations and potential shared key factors between COVID-19 and AD, with a focus on the ACE2 receptor, apolipo-protein E (APOE) genotype, age, and neuroinflammation.

关键词： sARs-CoV-2 COVID-19 Alzheimer’s disease ACE2 APOE Age Neuroinflammation

Immunotherapy for Alzheimer’s disease:targetingβ-amyloid and beyond

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Translational Neurodegeneration 2022年第1期11卷 690-706页

作者： Chenghuan song Jiyun shi Pingao Zhang Yongfang Zhang Jianrong Xu Lanxue Zhao Rui Zhang Hao Wang Hongzhuan Chen Department of Pharmacology and Chemical Biology Shanghai Jiao Tong University School of MedicineShanghai 200025China shanghai Universities Collaborative Innovation Center for Translational Medicine Shanghai Jiao Tong University School of MedicineShanghai 200025China Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education Shanghai Jiao Tong University School of MedicineShanghai 200025China Academy of Integrative Medicine Shanghai University of Traditional Chinese MedicineShanghai 201203China Department of Clinical Pharmacy Institute of Interdisciplinary Integrative Medicine ResearchShuguang HospitalShanghai University of Traditional Chinese MedicineShanghai 201203China.

Alzheimer’s disease(AD)is the most common neurodegenerative disease in the elderly worldwide.However,the complexity of AD pathogenesis leads to discrepancies in the understanding of this disease,and may be the main reason for the failure of AD drug development.Fortunately,many ongoing preclinical and clinical studies will continually open up avenues to unravel disease mechanisms and guide strategies for AD diagnosis and drug development.For example,immunotherapeutic strategies targeting amyloid-β(Aβ)and tau proteins were once deemed almost certainly effective in clinical treatment due to the excellent preclinical results.However,the repeated failures of clinical trials on vaccines and humanized anti-Aβand anti-tau monoclonal antibodies have resulted in doubts on this strategy.Recently,a new anti-Aβmonoclonal antibody(Aducanumab)has been approved by the Us Food and Drug Administration,which brings us back to the realization that immunotherapy strategies targeting Aβmay be still promising.Meanwhile,immunotherapies based on other targets such as tau,microglia and gut-brain axis are also under development.Further research is still needed to clarify the forms and epitopes of targeted proteins to improve the accuracy and effectiveness of immunotherapeutic drugs.In this review,we focus on the immunotherapies based on Aβ,tau and microglia and their mechanisms of action in AD.In addition,we present up-to-date advances and future perspectives on immunotherapeutic strategies for AD.

关键词： Alzheimer’s disease Immunotherapy Vaccine Antibody Drug development