Tau‐66: evidence for a novel tau conformation in Alzheimer's disease

Ghoshal, Nupur; Garcı́a-Sierra, Francisco; Fu, Yifan; Beckett, Laurel A.; Mufson, T. Elliott J.; Kuret, Jeff; Berry, Robert W.; Binder, Lester I.

doi:10.1046/j.1471-4159.2001.00346.x

Cited by 92 publications

(96 citation statements)

References 50 publications

(119 reference statements)

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“…Molecular mapping of the epitope of monoclonal antibody 423, that recognizes tau protein derived from AD brains, revealed for the first time that tau is truncated at E 391 in Alzheimer's disease [6,12]. Since then, truncation of tau was suggested by many authors as a possible seminal event in the pathogenesis of Alzheimer's disease [22][23][24]. It is generally agreed that tau has to undergo significant conformational change(s) leading to the pathological polymerization process.…”

Section: Discussionmentioning

confidence: 99%

Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo

Žilka¹,

Filipčík²,

Koson³

et al. 2006

FEBS Letters

225

203

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Truncated tau protein is the characteristic feature of human sporadic Alzheimer's disease. We have identified truncated tau proteins conformationally different from normal healthy tau. Subpopulations of these structurally different tau species promoted abnormal microtubule assembly in vitro suggesting toxic gain of function. To validate pathological activity in vivo we expressed active form of human truncated tau protein as transgene, in the rat brain. Its neuronal expression led to the development of the neurofibrillary degeneration of Alzheimer's type. Furthermore, biochemical analysis of neurofibrillary changes revealed that massive sarcosyl insoluble tau complexes consisted of human Alzheimer's tau and endogenous rat tau in ratio 1:1 including characteristic Alzheimer's disease (AD)-specific proteins (A68). This work represents first insight into the possible causative role of truncated tau in AD neurofibrillary degeneration in vivo.

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Section: Discussionmentioning

confidence: 99%

Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo

Žilka¹,

Filipčík²,

Koson³

et al. 2006

FEBS Letters

225

203

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“…Immunostaining was performed on 40-m-thick frozen sections of human hippocampus from AD brain provided by the Neuropathology Core of the Northwestern University Cognitive Neurology and Alzheimer's Disease Center. Brightfield and laser-scanning confocal microscopy were performed as described (28). For brightfield microscopy, Tau5 was used at 20 ng͞ml, and a tissue culture supernatant containing TauC3 was used at a dilution of 1:2,500.…”

Section: Expression Of Recombinant Wt or Truncated Tau Proteins In Esmentioning

confidence: 99%

Caspase cleavage of tau: Linking amyloid and neurofibrillary tangles in Alzheimer's disease

Gamblin

Chen

Zambrano

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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755

834

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The principal pathological features of Alzheimer's disease (AD) are extracellular amyloid plaques and intracellular neurofibrillary tangles, the latter composed of the microtubule-binding protein tau assembled into paired helical and straight filaments. Recent studies suggest that these pathological entities may be functionally linked, although the mechanisms by which amyloid deposition promotes pathological tau filament assembly are poorly understood. Here, we report that tau is proteolyzed by multiple caspases at a highly conserved aspartate residue (Asp 421 ) in its C terminus in vitro and in neurons treated with amyloid-␤ (A␤) (1-42) peptide. Tau is rapidly cleaved at Asp 421 in A␤-treated neurons (within 2 h), and its proteolysis appears to precede the nuclear events of apoptosis. We also demonstrate that caspase cleavage of tau generates a truncated protein that lacks its C-terminal 20 amino acids and assembles more rapidly and more extensively into tau filaments in vitro than wild-type tau. Using a monoclonal antibody that specifically recognizes tau truncated at Asp 421 , we show that tau is proteolytically cleaved at this site in the fibrillar pathologies of AD brain. Taken together, our results suggest a novel mechanism linking amyloid deposition and neurofibrillary tangles in AD: A␤ peptides promote pathological tau filament assembly in neurons by triggering caspase cleavage of tau and generating a proteolytic product with enhanced polymerization kinetics. A lzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by accelerated neuronal cell death leading to dementia (1). Its hallmark pathologic features are extracellular amyloid plaques and intraneuronal fibrillar structures, the latter including neurofibrillary tangles (NFTs), neuropil threads, and dystrophic neurites invading amyloid plaques (2). Amyloid plaques are formed by the extracellular deposition of proteolytic fragments of the amyloid precursor protein (APP) termed amyloid-␤ (A␤) (1, 3), whereas the fibrillar pathologies are composed of the microtubule-associated protein tau assembled into polymeric filaments (paired helical and straight filaments) (2). The pathogenic role of amyloid deposition in AD is underscored by the evidence that each of the disease-causing mutations in familial AD results in enhanced production of amyloidogenic A␤ peptides; these peptides are sufficient to induce apoptosis in cultured neurons (1, 3). Furthermore, the recent observation that tau mutations cause hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), a class of diseases characterized by NFT-like deposition of polymeric tau and dementia without amyloid plaques, emphasizes the critical role that tau plays in neurodegenerative events (4-6). Although amyloid plaques and NFTs have been largely regarded as independent neuropathologic entities, recent work suggests they may be functionally linked: mutation of APP that results in amyloid deposition or direct intracranial injection of A␤ peptide increase...

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“…32 The evolution of tau pathology is marked by a set of modifications (eg, phosphorylations and truncations) that progress linearly in neurons of the entorhinal cortex, hippocampus, and temporal cortex in AD. [27][28][29][30][31][32] Specifically, the early phosphorylation event at serine 422 (identified by the pS422 antibody) is followed by the truncation at the caspase cleavage sight, aspartic acid 421 (identified by the TauC3 antibody). 30,32 In the medial temporal lobe, there is a much greater proportion of pS422 labeled neurons compared with TauC3 in cases designated as Braak stages I and II.…”

Section: Nft Formation In the Cbf Is Slower Than In Other Cortical Rementioning

confidence: 99%

“…Posttranslational phosphorylation [23][24][25] and truncation 26 events are thought to contribute to tau conformational changes [27][28][29] that accelerate the formation of filaments leading to NFTs. A linear model for NFT evolution has been proposed, which can be tracked by antibodies to tau epitopes marking early, intermediate, and late stages of NFT development in the hippocampus, temporal, and frontal cortex during the progression of AD.…”

mentioning

confidence: 99%

“…A linear model for NFT evolution has been proposed, which can be tracked by antibodies to tau epitopes marking early, intermediate, and late stages of NFT development in the hippocampus, temporal, and frontal cortex during the progression of AD. [27][28][29][30][31][32] Phosphorylation at Ser422 was identified as an early event using the pS422 antibody, whereas truncation at the caspase cleavage site (Asp421) identified with the TauC3 antibody, occurred later during the onset of NFT formation. 30,32,33 In the present study, these site-specific tau antibodies were used to gain a greater understanding of tangle evolution within the NB neurons during the onset of AD.…”

mentioning

confidence: 99%

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Progression of Tau Pathology in Cholinergic Basal Forebrain Neurons in Mild Cognitive Impairment and Alzheimer's Disease

Vana

Kanaan

Ugwu

et al. 2011

The American Journal of Pathology

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112

109

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Tau is a microtubule-associated protein that forms neurofibrillary tangles (NFTs) in the selective vulnerable long projection neurons of the cholinergic basal forebrain (CBF) in Alzheimer's disease (AD). Although CBF neurodegeneration correlates with cognitive decline during AD progression, little is known about the temporal changes of tau accumulation in this region. We investigated tau posttranslational modifications during NFT evolution within the CBF neurons of the nucleus basalis (NB) using tissue from subjects with no cognitive impairment, mild cognitive impairment, and AD. The pS422 antibody was used as an early tau pathology marker that labels tau phosphorylated at Ser422; the TauC3 antibody was used to detect later stage tau pathology. Stereologic evaluation of NB tissue immunostained for pS422 and TauC3 revealed an increase in neurons expressing these tau epitopes during disease progression. We also investigated the occurrence of pretangle tau events within cholinergic NB neurons by dual staining for the cholinergic cell marker, p75 NTR , which displays a phenotypic down-regulation within CBF perikarya in AD. As pS422؉ neurons increased in number, p75 NTR ؉ neurons decreased, and these changes correlated with both AD neuropathology and cognitive decline. Also, NFTs developed slower in the CBF compared with previously examined cortical regions. Taken together, these results suggest that changes in cognition are associated with pretangle events within NB cholinergic neurons before frank Degeneration of the cholinergic basal forebrain (CBF) neurons, which provide the major cholinergic innervation to the entire cortical mantle, hippocampus, and amygdala 1,2 correlates with dementia severity, disease duration, and cognitive impairment 3,4 in Alzheimer's disease (AD). 3,5-9 The viability of CBF neurons is dependent on the prototypic neurotrophic substance, nerve growth factor (NGF), 10 which is retrogradely transported to CBF neurons through a complex interaction of its two receptors, the high-affinity NGF-specific cell survival tyrosine kinase (trkA) and the putative cell death associated lowaffinity pan neurotrophin (p75 NTR ) receptor. 11,12 Previous studies have identified critical changes within the basocortical cholinergic system during the progression of AD, indicating a shift in the balance from pro-survival to apoptotic mechanisms, before frank cellular alteration, 13,14 which likely over time plays a mechanistic role in the CBF degeneration seen in AD. 5 In addition to altered neurotrophic factor dysfunction coincident with disease progression, CBF neurons also develop intracellular inclusions that appear as globose neurofibrillary tangles (NFTs) and neuropil threads (NTs), hallmark tau pathologies found in AD. [15][16][17] Tau is a microtubule-associated protein involved in normal cytoskeleton function, 18,19 but in AD tau transitions from its relatively soluble state into filamentous aggregates. 20 Braak and colleagues delineated six stages (I to VI) related to the spatial temporal distribution a...

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Tau‐66: evidence for a novel tau conformation in Alzheimer's disease

Cited by 92 publications

References 50 publications

Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo

Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo

Caspase cleavage of tau: Linking amyloid and neurofibrillary tangles in Alzheimer's disease

Progression of Tau Pathology in Cholinergic Basal Forebrain Neurons in Mild Cognitive Impairment and Alzheimer's Disease

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