Alzheimer disease tangles share immunological similarities with multiphosphorylation repeats in the two large neurofilament proteins.

Lee, V. M.-Y.; Ötvös, László; Schmidt, Maria Luiza Gava; Trojanowski, John Q.

doi:10.1073/pnas.85.19.7384

Cited by 104 publications

(59 citation statements)

References 27 publications

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“…Recently, we described α-internexin as a major component of the pathological hallmark of NIFID [5]. Although previous studies have demonstrated the co-localization of NF epitopes in AD, PD, DLB, and MND [19,25,26,28,29,32,33,34,35], no study has demonstrated the presence of α-internexin as a component of the pathological inclusions of any neurodegenerative disease other than NIFID.…”

Section: Introductionmentioning

confidence: 87%

“…This study using a panel of anti-IF proteins has confirmed and extended our earlier observations that all class IV IF proteins are present within the inclusions of NIFID [5], while epitopes of classes III, V, and VI IFs are absent from the inclusions of NIFID. Previously we have shown that epitopes of NF proteins are present within the pathological inclusions of several neurodegenerative disorders including AD, PD, DLB, and MND [19,26,32,33,34,35]. Here, we report for the first time that α-internexin is also present in small subsets of the pathological neuronal inclusions of AD, PD, DLB, FTLD-MND, and rarely in the swollen axons and spheroids of MND, non-tau FTDs, and normal aged brain.…”

Section: Discussionmentioning

confidence: 99%

“…Anti-NF antibodies used in this study are well characterized and have been used previously to demonstrate epitopes of NF in neuronal inclusions in AD, Lewy body diseases, and MND [6,19,25,26,32,33,34,35]. In addition, antibodies to α-synuclein [10], cytoskeletal, and other proteins associated with abnormal protein aggregates in neurodegenerative diseases were used in this study.…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

“…The use of phosphorylation-dependent and -independent antibodies to NF epitopes has enabled the immunohistochemical dissection of these proteins and has revealed that NFs within the perikaryon and proximal segments of axons and dendrites are normally hypophosphorylated, while NFs in axons are heavily phosphorylated. In neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies (DLB) and motor neuron disease (MND), abnormal accumulations of phosphorylated NF proteins in the cell body have been reported [19,26,28,29,32,33,34,35], although the significance of the phosphorylation of NF proteins within the cytoplasm is unclear. However, abnormal phosphorylation may impede axonal transport and contribute to neuronal dysfunction, while constitutive phosphorylation of NFs may protect them against proteolysis [17].…”

Section: Introductionmentioning

confidence: 99%

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?-Internexin aggregates are abundant in neuronal intermediate filament inclusion disease (NIFID) but rare in other neurodegenerative diseases

et al. 2004

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Abnormal neuronal aggregates of α-internexin and the three neurofilament (NF) subunits, NF-L, NF-M, and NF-H have recently been identified as the pathological hallmarks of neuronal intermediate filament (IF) inclusion disease (NIFID), a novel neurological disease of early onset with a variable clinical phenotype including frontotemporal dementia, pyramidal and extrapyramidal signs. α-Internexin, a class IV IF protein, a major component of inclusions in NIFID, has not previously been identified as a component of the pathological protein aggregates of any other neurodegenerative disease. Therefore, to determine the specificity of this protein, α-internexin immunohistochemistry was undertaken on cases of NIFID, non-tau frontotemporal

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Section: Introductionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

?-Internexin aggregates are abundant in neuronal intermediate filament inclusion disease (NIFID) but rare in other neurodegenerative diseases

et al. 2004

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“…I n A D a n d o t h e r t a u o p a t h i e s s u c h a s F T D , hyperphosphorylated tau accumulates within neurons in the form of neurofibrillary tangles [126][127][128][129][130][131]. Importantly, as cognitive impairments closely correlate with the extension of tau pathology [132,133], removing neurofibrillary tangles has become one of the main therapeutic goals for the treatment of AD and FTD [134,135].…”

Section: Immunotherapy Targeting Taumentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-β, α-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-β in Alzheimer's disease, α-synuclein in Alzheimer's disease and Parkinson's disease, and tau in Alzheimer's disease and frontotemporal dementia.

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Human fetal hippocampal development: II. The neuronal cytoskeleton

Arnold

Trojanowski

1996

J. Comp. Neurol.

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In this study of the developing human hippocampus, we monitor the timing of onset and the sequential patterns of expression of 11 developmentally regulated proteins that are important components of the neuronal cytoskeleton. Immunohistochemistry using well-characterized antibodies was conducted with fixed paraffin-embedded sections from hippocampi at various stages of fetal and postnatal development. At 9 weeks gestational age, immunoreactivity was evident for the microtubule-associated proteins (MAPs), MAP2 and MAP5, low molecular weight (Mr) neurofilament (NF) protein (NF-L), poorly phosphorylated mid-Mr NF protein (NF-M/P-), vimentin, and alpha-and beta-tubulins within the somatodendritic domain of neurons of the hippocampal plate. Weak immunoreactivity for moderately phosphorylated, high Mr NF protein (NF-H/P + + +), tau, and nestin was observed. Highly phosphorylated mid-Mr NF protein (NF-M/P + + +) and alpha-internexin were first detected at 15 weeks and highly phosphorylated, high Mr NF protein (NF-H/P+3) at 20 weeks. At 15 weeks, MAP2, MAP5, and tubulins were expressed in an "inside-out" gradient and in a gradient between hippocampal subfields with subiculum > ammonic subfields > dentate gyrus. These gradients paralleled the maturational gradients seen in cytoarchitectural and neuronal morphologic studies. The adult pattern of neuronal cytoskeletal protein expression in the hippocampus was attained by the second postnatal year for all proteins. Our findings demonstrate an elaborate orchestration of cytoskeletal protein expression within the hippocampus that is qualitatively similar to what is seen in other brain regions and in nonhuman species but which also has some important differences in timing and pattern. The differences in the developmentally regulated expression of neuronal cytoskeletal proteins in separate regions of the central nervous system (CNS) suggest that there are region-specific differences in composition and function of the neuronal cytoskeleton. These observations have implications for understanding the role of the neuronal cytoskeleton in the developing, mature, and diseased CNS.

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Alzheimer disease tangles share immunological similarities with multiphosphorylation repeats in the two large neurofilament proteins.

Cited by 104 publications

References 27 publications

?-Internexin aggregates are abundant in neuronal intermediate filament inclusion disease (NIFID) but rare in other neurodegenerative diseases

?-Internexin aggregates are abundant in neuronal intermediate filament inclusion disease (NIFID) but rare in other neurodegenerative diseases

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Human fetal hippocampal development: II. The neuronal cytoskeleton

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