Tau is essential to -amyloid-induced neurotoxicity (original) (raw)
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American Journal Of Pathology
Farmnacoln(yiche Mario NegriJ, (r Milano, Italy; ancl the I)epartment of Pathology,;, New York Unoiversity Medical Genter, Newa York, Nel,i Y'ork Extracellular deposition of amyloid fibrils and intraneuronal accumulation ofpaired helicalfilaments (PHFs) are tbe neuropathological hallmarks ofAlzheimer's disease. The major constituent of amyloid fibrils is a 39to 43-residue peptide (termed A (), which is derived from a 695to 770-amino-acid precursor protein (termed f3PP). The main component of PHFs identified so far is the microtubule-associated protein tau. Yet, there is no direct evidence of interconnection between these two pathological states. We report here that antibodies to an epitope located between residues 713 and 723 of f3PP770 (ie, the transmembrane region of f3PP distal to A08) consistently labeled PHFs in the brain of Alzheimer patients. Solid phase immunoassay showed that a peptide homologous to residues 713 to 730 of f6PP770 bound tau pro-teins. This f3PP peptide spontaneously formed fibrils in vitro and, in the presence of tau, generated dense fibrillary assemblies containing both molecules. These data suggest that .BPP or f3PPfragments containing the tau binding site are involved in the pathogenesis of PHFs in Alzbeimer's disease. (Am J Pathol 1996, 148:79-87) The co-occurrence of AP3 deposits and neurofibrillary tangles (NFTs) with paired helical filaments (PHFs) is the hallmark of Alzheimer's disease (AD). AP3 deposition takes place in the neuropil and in leptomeningeal and cortical vessels, whereas PHF formation occurs within perikarya and neurites of selected neuronal populations.1 AP3 is a 39to 43-residue peptide derived by proteolytic cleavage of 695to 770-amino-acid membrane-associated glycoproteins (O3PP) with structural features of an integral transmembrane receptor in which AP3 is positioned partly in the extracellular domain and partly in the transmembrane domain ( ).2--8 PHFs are composed primarily of tau proteins,9-15 microtubule-associated proteins of 352 to 441 amino acids, with a characteristic sequence of three or four tandem repeats in the carboxyl-terminal domain implicated in tubulin binding.12'13 Evidence indicates that the PHF-tau is abnormally phosphorylated10-15 and is incorporated into the filaments in such a way that the tubulin-
Alzheimer's Disease Pathogenesis-Core Concepts, Shifting Paradigms and Therapeutic Targets, 2011
The description about the progression of the neurofibrillary pathology in AD has been proposed by Braak and Braak (Braak et al., 1993, 1996), which states that there is a stereotype in the appearance and distribution of NFTs along entorhinal, limbic and isocortical areas. It is well known that in AD, NFTs and dystrophic neurites (DNs) are mostly composed of tau protein which has undergone several posttranslational modifications such as abnormal phosphorylation, conformational changes and truncation (Du et al., 2007; Novak et al., 1991; Wischik et al., 1988a). In this regard, we have previously proposed that a continuous and specific pathway of conformational changes and truncation of tau protein is occurring during the maturation of NFTs (
European Neurological Review, 2009
In Alzheimer’s disease, tau protein is abnormally processed to self-aggregate into pathologically paired helical filaments and neurofibrillary tangles. Accumulation of these structures in the somatodendritic compartment of neurons may result in pathological alterations of the cytoskeleton stability, abnormal sorting of molecules and obstruction of the intracellular transport of organelles. Initially, abnormal phosphorylation of tau was considered by many to be the major modification that alters its microtubule-binding capacity. In recent years, however, proteolytic cleavage of tau protein produced by caspases has been shown to promote the abnormal aggregation properties of tauin vitroand to produce toxic effects in cell and animal models of Alzheimer's disease. Although some of these results have been debated, truncation of tau associated with neurofibrillary tangle formation has been shown to correlate well with the clinical progression of Alzheimer’s disease. Although new alte...
Neurobiological pathways to Alzheimer’s disease. Amyloid-beta, Tau protein or both?
Dementia Neuropsychologia, 2009
Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, including memory loss, behavioral and psychological symptoms and personality changes. The neuropathological hallmarks of AD are the presence of neuritic (senile) plaques (NP) and neurofibrillary tangles (NFT), along with neuronal loss, dystrophic neurites, and gliosis. Neuritic plaques are extracellular lesions and their main constituent is the amyloid-β 42 peptide (Aβ 42 ). Neurofibrillary tangles are intracellular lesions that are mainly composed of hyperphosphorylated TAu protein. In this article, we review the major hypotheses concerning the physiopathology of AD, focusing on the β-amyloid cascade as primary events (supported by the "βaptists") and cytoskeletal abnormalities secondary to the hyperphosphorylation of protein TAu (as advocated by the "Tauists"). We further provide an integrative view of the physiopathology of AD.
The American journal of pathology, 1996
Extracellular deposition of amyloid fibrils and intraneuronal accumulation of paired helical filaments (PHFs) are the neuropathological hallmarks of Alzheimer's disease. The major constituent of amyloid fibrils is a 39- to 43-residue peptide (termed A beta), which is derived from a 695- to 770-amino-acid precursor protein (termed beta PP). The main component of PHFs identified so far is the microtubule-associated protein tau. Yet, there is no direct evidence of interconnection between these two pathological states. We report here that antibodies to an epitope located between residues 713 and 723 of beta PP770 (ie, the transmembrane region of beta PP distal to A beta) consistently labeled PHFs in the brain of Alzheimer patients. Solid phase immunoassay showed that a peptide homologous to residues 713 to 730 of beta PP770 bound tau proteins. This beta PP peptide spontaneously formed fibrils in vitro and, in the presence of tau, generated dense fibrillary assemblies containing both...
Role of tau in Alzheimer’s dementia and other neurodegenerative diseases
Alzheimer’s disease (AD) is defined histopathologically by beta-amyloid (Aβ) senile plaques andneurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. The question as to which of theselesions takes precedence in AD pathology has long been an issue of debate. The amyloid cascadehypothesis, currently the predominant hypothesis, considers Aβ peptide to be responsible for the majorneurodegeneration observed in AD while the cytoskeleton hypothesis states that tauhyperphosphorylation and subsequent aggregation may be central to the neurodegeneration observed inAD. This review focuses on tau mutations, phosphorylation sites, tau isoforms and theneurohistopathology of AD, and three other tauopathies to demonstrate that disease progression andneuronal loss in AD correlate also with pathological tau and not just amyloid deposition. Although tau isat the center of all these neurodegenerative diseases, there exist differences in morphology, isoforms,phosphorylation sites and mutatio...