AD2, a phosphorylation-dependent monoclonal antibody directed against tau proteins found in Alzheimer's disease

Islet-brain1 (IB1) or c-Jun NH2 terminal kinase interacting protein-1 (JIP-1), the product of the MAPK8IP1 gene, functions as a neuronal scaffold protein to allow signalling specificity. IB1/ JIP-1 interacts with many cellular components including the reelin receptor ApoER2, the lowdensity lipoprotein receptor-related protein (LRP), kinesin and the Alzheimer's amyloid precursor protein. Coexpression of IB1/JIP-1 with other components of the c-Jun NH2 terminal-kinase (JNK) pathway activates the JNK activity; conversely, selective disruption of IB1/JIP-1 in mice reduces the stress-induced apoptosis of neuronal cells. We therefore hypothesized that IB1/JIP-1 is a risk factor for Alzheimer's disease (AD). By immunocytochemistry, we first colocalized the presence of IB1/JIP-1 with JNK and phosphorylated tau in neurofibrillary tangles. We next identified a À499A4G polymorphism in the 5' regulatory region of the MAPK8IP1 gene. In two separate French populations the À499A4G polymorphism of MAPK8IP1 was not associated with an increased risk to AD. However, when stratified on the þ 766C4T polymorphism of exon 3 of the LRP gene, the IB1/JIP-1 polymorphism was strongly associated with AD in subjects bearing the CC genotype in the LRP gene. The functional consequences of the -499A4G polymorphism of MAPK8IP1 was investigated in vitro. In neuronal cells, the G allele increased transcriptional activity and was associated with an enhanced binding activity. Taken together, these data indicate that the increased transcriptional activity in the presence of the G allele of MAPK8IP1 is a risk factor to the onset of in patients bearing the CC genotype of the LRP gene.

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“…25,32,37,38 The phosphorylated tau proteins are typically found in AD. 39 AD2 antibody was kindly provided by C Mourton-Gilles.…”

Section: Antibodiesmentioning

confidence: 99%

Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease

et al. 2003

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“…AT100 was used to detect abnormal Tau phosphorylation [2]. Finally, M19G is a well-characterised anti-serum, directed against the ¢rst 19 amino acids of the tau sequence encoded by exon 1 [18] that recognises its epitope independently of the Tau phosphorylation state.…”

Section: Antibodiesmentioning

confidence: 99%

Modelling Alzheimer‐specific abnormal Tau phosphorylation independently of GSK3β and PKA kinase activities

et al. 2002

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In Alzheimer's disease, neurofibrillary degeneration results from the aggregation of abnormally phosphorylated Tau proteins into paired helical filaments. These Tau variants displayed specific epitopes that are immunoreactive with antiphospho-Tau antibodies such as AT100. As shown in in vitro experiments, glycogen synthase kinase 3 L L (GSK3L L) and protein kinase A (PKA) may be key kinases in these phosphorylation events. In the present study, Tau was microinjected into Xenopus oocytes. Surprisingly, in this system, AT100 was generated without any GSK3L L and PKA contribution during the progesterone or insulin-induced maturation process. Our results demonstrate that a non-modified physiological process in a cell model can generate the most specific Alzheimer epitope of Tau pathology. ß

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“…The following anti-tau antibodies were used: PHF-1 (Greenberg et al, 1992;Otvos et al, 1994) (a kind gift from Dr. Peter Davies, Albert Einstein College of Medicine, New York, NY), AD2 (BueeScherrer et al, 1996) (Bio-Rad, Hercules, CA), glial fibrillary acidic protein (GFAP) (PharMingen, San Diego, CA), AT-8 (Biernat et al, 1992;Mercken et al, 1992) (Innogenetics, Gent, Belgium), cleaved caspase-3 (Cell Signaling Technology, Beverly, MA), anti-GSK-3␣/␤ (Biosource, Camarillo, CA), anti-myc (Developmental Studies Hybridoma Bank, Iowa City, IA), and anti-␤-tubulin (Sigma). According to the residue numbering of the longest human tau isoform of 441 aa, antibody PHF-1 and AD2 can react with tau when serines 396 and 404 are phosphorylated (Buee-Scherrer et al, 1996), although it has also been reported that the presence of phosphorylated Ser396 in tau protein appears to be sufficient for AD2 recognition and that phosphorylation in Ser404 seems not to play a major role in this binding (Torreilles et al, 2000) and the AT-8 antibody recognizes tau when Ser202 and Thr205 are phosphorylated (Goedert et al, 1995). The 7.51 antibody recognizes segments of the last two repeats within the microtubule binding domain of tau in a phosphorylation-independent manner (Novak et al, 1991) and detects all soluble tau isoforms in Western blot analysis and unbound tau in immunohistochemical analysis.…”

Section: Methodsmentioning

confidence: 99%

Full Reversal of Alzheimer's Disease-Like Phenotype in a Mouse Model with Conditional Overexpression of Glycogen Synthase Kinase-3

Engel¹,

Hernández²,

Ávila³

et al. 2006

J. Neurosci.

234

182

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Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase that is particularly abundant in the CNS. Dysregulation of GSK-3 activity is believed to play a key role in the pathogenesis of CNS chronic disorders such as Alzheimer's disease (AD), bipolar disorder, and Huntington's disease, and of metabolic disorders such as type II diabetes. Accordingly, GSK-3 inhibitors have been postulated as therapeutic tools for these diseases. Interestingly, pathophysiological and pharmacological regulation of GSK-3 is affected by an amplification mechanism that applies both to inhibition and activation. The possibility therefore exists that sustained inhibition or activation might persist after cessation of the initial trigger. Regarding AD, GSK-3 has been shown to accumulate in pretangle neurons. Furthermore, GSK-3 phosphorylates tau in most serine and threonine residues hyperphosphorylated in PHF (paired helical filament)-tau and GSK-3 activity contributes both to ␤-amyloid production and to ␤-amyloid-mediated neuronal death. In good agreement, mice with conditional overexpression of GSK-3 in forebrain neurons (Tet/GSK-3␤ mice) recapitulate aspects of AD neuropathology such as tau hyperphosphorylation, apoptotic neuronal death, and reactive astrocytosis as well as spatial learning deficit. Here, we exploit the conditional system used to generate Tet/GSK-3␤ mice to explore whether the biochemical, histopathological, and behavioral consequences of increased GSK-3 activity are susceptible to revert after restoration of normal GSK-3 levels. Here, we show that transgene shutdown in symptomatic mice leads to normal GSK-3 activity, normal phospho-tau levels, diminished neuronal death, and suppression of the cognitive deficit, thus further supporting the potential of GSK-3 inhibitors for AD therapeutics.

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AD2, a phosphorylation-dependent monoclonal antibody directed against tau proteins found in Alzheimer's disease

Cited by 146 publications

References 43 publications

Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease

Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease

Modelling Alzheimer‐specific abnormal Tau phosphorylation independently of GSK3β and PKA kinase activities

Full Reversal of Alzheimer's Disease-Like Phenotype in a Mouse Model with Conditional Overexpression of Glycogen Synthase Kinase-3

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