N-terminally truncated Aβ4-x proteoforms and their relevance for Alzheimer’s pathophysiology  

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作  者:Agueda Rostagno Erwin Cabrera Tammaryn Lashley Jorge Ghiso 

机构地区:[1]Departments of Pathology,New York University School of Medicine,New York,NY 10016,USA [2]The Queen Square Brain Bank for Neurological Disorders,Department of Clinical and Movement Neurosciences,UCL Queen Square Institute of Neurology,London WC1N 3BG,UK [3]Department of Neurodegenerative Disease,UCL Queen Square Institute of Neurology,London WC1N 3BG,UK [4]Departments of Psychiatry,New York University School of Medicine,550 First Avenue,New York,NY 10016,USA [5]Current affiliation:Farmingdale State College,State University of New York,Farmingdale,NY 11735,USA.

出  处:《Translational Neurodegeneration》2022年第1期496-513,共18页转化神经变性病(英文)

基  金:the National Institutes of Health AG051266,AG059695,and AG065651(to JG);from the Bright Focus Foundation A2015275S(to JG).

摘  要:Background:The molecular heterogeneity of Alzheimer’s amyloid-β(Aβ)deposits extends well beyond the clas-sic Aβ1-40/Aβ1-42 dichotomy,substantially expanded by multiple post-translational modifications that increase the proteome diversity.Numerous truncated fragments consistently populate the brain Aβpeptidome,and their homeo-static regulation and potential contribution to disease pathogenesis are largely unknown.Aβ4-x peptides have been reported as major components of plaque cores and the limited studies available indicate their relative abundance in Alzheimer’s disease(AD).Methods:Immunohistochemistry was used to assess the topographic distribution of Aβ4-x species in well-char-acterized AD cases using custom-generated monoclonal antibody 18H6-specific for Aβ4-x species and blind for full-length Aβ1-40/Aβ1-42-in conjunction with thioflavin-S and antibodies recognizing Aβx-40 and Aβx-42 proteo-forms.Circular dichroism,thioflavin-T binding,and electron microscopy evaluated the biophysical and aggregation/oligomerization properties of full-length and truncated synthetic homologues,whereas stereotaxic intracerebral injections of monomeric and oligomeric radiolabeled homologues in wild-type mice were used to evaluate their brain clearance characteristics.Results:All types of amyloid deposits contained the probed Aβepitopes,albeit expressed in different proportions.Aβ4-x species showed preferential localization within thioflavin-S-positive cerebral amyloid angiopathy and cored plaques,strongly suggesting poor clearance characteristics and consistent with the reduced solubility and enhanced oligomerization of their synthetic homologues.In vivo clearance studies demonstrated a fast brain efflux of N-termi-nally truncated and full-length monomeric forms whereas their oligomeric counterparts-particularly of Aβ4-40 and Aβ4-42-consistently exhibited enhanced brain retention.Conclusions:The persistence of aggregation-prone Aβ4-x proteoforms likely contributes to the process of amyloid formation,self-perp

关 键 词:Alzheimer’s disease Amyloid-βtruncated species Peptide oligomerization Brain clearance Brain efflux Stereotaxic intracerebral injection 

分 类 号:R749.16[医药卫生—神经病学与精神病学]

 

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