Alz‐50 Antibody recognizes alzheimer‐related neuronal changes

Hyman, B. T.; Hoesen, Gary W. Van; Wolozin, Benjamin; Davies, Peter; Kromer, L. J.; Damasio, A. R.

doi:10.1002/ana.410230410

Cited by 171 publications

(83 citation statements)

References 37 publications

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“…To define whether the Tau-nY29 epitope colocalizes with markers of early stage tau pathology, we also performed doublelabel studies in which Tau-nY29 was paired with the antibody Alz-50. Alz-50 is a conformation-dependent probe that recognizes early filamentous changes in tau (Hyman et al, 1988;Carmel et al, 1996). Qualitatively, we found that the Tau-nY29 and Alz-50 antibodies colocalize to an appreciable extent in the NFTs of severe AD cases.…”

Section: Tau-ny29 Labels the Fibrillar Lesions Of Ad And Other Non-admentioning

confidence: 65%

Tau Nitration Occurs at Tyrosine 29 in the Fibrillar Lesions of Alzheimer's Disease and Other Tauopathies

Reynolds¹,

Reyes²,

Fu³

et al. 2006

J. Neurosci.

121

105

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The neurodegenerative tauopathies are a clinically diverse group of diseases typified by the pathological self-assembly of the microtubule-associated tau protein. Although tau nitration is believed to influence the pathogenesis of these diseases, the precise residues modified, and the resulting effects on tau function, remain enigmatic. Previously, we demonstrated that nitration at residue Tyr29 markedly inhibits the ability of tau to self-associate and stabilize the microtubule lattice (Reynolds et al., 2005b, 2006). Here, we report the first monoclonal antibody to detect nitration in a protein-specific and site-selective manner. This reagent, termed Tau-nY29, recognizes tau only when nitrated at residue Tyr29. It does not cross-react with wild-type tau, tau mutants singly nitrated at Tyr18, Tyr197, and Tyr394, or other proteins known to be nitrated in neurodegenerative diseases. By Western blot analysis, Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology. Collectively, our findings provide the first direct evidence that site-specific tau nitration is linked to the progression of the neurodegenerative tauopathies.

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Section: Tau-ny29 Labels the Fibrillar Lesions Of Ad And Other Non-admentioning

confidence: 65%

Tau Nitration Occurs at Tyrosine 29 in the Fibrillar Lesions of Alzheimer's Disease and Other Tauopathies

Reynolds¹,

Reyes²,

Fu³

et al. 2006

J. Neurosci.

121

105

View full text Add to dashboard Cite

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“…Abnormal conformations of tau, recognized by specific antibodies such as Alz50 and MC1, have been associated with degeneration and can be detected before the appearance of neurofibrillary pathology (Hyman et al, 1988;Jicha et al, 1999a). Notably, tau phosphorylation may help stabilize these aberrant conformations (Carmel et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…18, December 2007To examine whether single site phosphorylation affects the appearance of disease-specific conformations of tau, we used the antibodies MC1 and Alz50, which recognize abnormal conformations of tau associated with Alzheimer's disease and related disorders (Hyman et al, 1988;Carmel et al, 1996;Vincent et al, 1996). Immunostaining of retinal sections with MC1 yielded no signal for nontransgenic control flies ( Figure 3A), but it detected equivalent levels of immunoreactivity in tau WT (3B), and flies expressing the individual points mutants.…”

Section: Single Phosphoepitopes and Tau Toxicitymentioning

confidence: 99%

Tau Phosphorylation Sites Work in Concert to Promote Neurotoxicity In Vivo

Steinhilb

Dias‐Santagata

Fulga

et al. 2007

MBoC

174

130

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Tau is a microtubule binding protein implicated in a number of human neurodegenerative disorders, including Alzheimer's disease. Phosphorylation of serine-proline/threonine-proline sites, targeted by proline-directed kinases, coincides temporally with neurodegeneration in the human diseases. Recently, we demonstrated that this unique group of serines and threonines has a critical role in controlling tau toxicity in a Drosophila model of tauopathy. Here, we use a combination of genetic and biochemical approaches to examine these sites individually and to determine which of them is primarily responsible for controlling tau neurotoxicity. Despite the importance placed on individual phosphoepitopes and their contributions to disease pathogenesis, our results indicate that no single phosphorylation residue plays a dominant role in controlling tau toxicity. These findings suggest that serine-proline/threonine-proline sites cooperate to mediate neurodegeneration in vivo.

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“…The N-terminal 15 amino acids of tau are required for the formation of the Alz-50 conformation of tau (Carmel et al, 1996;Jicha et al, 1997), a conformation known to be a marker for early tangles (Hyman et al, 1988;Ghoshal et al, 2002;García-Sierra et al, 2003). The Alz-50 conformation of tau is gradually replaced by another conformation in tangles, Tau-66 (Ghoshal et al, 2001;García-Sierra et al, 2003), which does not require an intact N terminus.…”

Section: Timing and Significance Of N-terminal Cleavagementioning

confidence: 99%

Early N-Terminal Changes and Caspase-6 Cleavage of Tau in Alzheimer's Disease

Horowitz¹,

Patterson²,

et al. 2004

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Alzheimer's disease (AD) is a progressive amnestic dementia that involves post-translational hyperphosphorylation, enzymatic cleavage, and conformational alterations of the microtubule-associated protein tau. The truncation state of tau influences many of its pathologic characteristics, including its ability to assume AD-related conformations and to assemble into filaments. Cleavage also appears to be an important marker in AD progression. Although C-terminal truncation of tau at D421 has recently been attributed to the apoptotic enzyme caspase-3, N-terminal processing of the protein remains mostly uncharacterized. Here, we report immunohistochemical staining in a cohort of 35 cases ranging from noncognitively impaired to early AD with a panel of three N-terminal anti-tau antibodies: Tau-12, 5A6, and 9G3-pY18. Of these three, the phosphorylation-independent epitope of 5A6 was the earliest to emerge in the pathological lesions of tau, followed by the appearance of the Tau-12 epitope. The unmasking of the Tau-12 epitope in more mature 5A6-positive tangles was not correlated with tau phosphorylation at tyrosine 18 (9G3-pY18). Still, later in the course of tangle evolution, the extreme N terminus of tau was lost, correlating temporally with the appearance of a C-terminal caspase-truncated epitope lacking residues 422-441. In addition, caspase-6 cleaved the N terminus of tau in vitro, preventing immunoreactivity with both Tau-12 and 5A6. Mass spectrometry confirmed that the in vitro caspase-6 truncation site is D13, a semicanonical and hitherto undescribed caspase cleavage site in tau. Collectively, these results suggest a role for caspase-6 and N-terminal truncation of tau during neurofibrillary tangle evolution and the progression of Alzheimer's disease.

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Alz‐50 Antibody recognizes alzheimer‐related neuronal changes

Cited by 171 publications

References 37 publications

Tau Nitration Occurs at Tyrosine 29 in the Fibrillar Lesions of Alzheimer's Disease and Other Tauopathies

Tau Nitration Occurs at Tyrosine 29 in the Fibrillar Lesions of Alzheimer's Disease and Other Tauopathies

Tau Phosphorylation Sites Work in Concert to Promote Neurotoxicity In Vivo

Early N-Terminal Changes and Caspase-6 Cleavage of Tau in Alzheimer's Disease

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