Molecular Mechanism of Alzheimer's Neurofibrillary Degeneration and Therapeutic Interventiona

Iqbal, Khalid; Grundke‐Iqbal, Inge

doi:10.1111/j.1749-6632.1996.tb34411.x

Cited by 35 publications

(14 citation statements)

References 21 publications

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“…The hyperphosphorylation of tau impairs its binding capacity to microtubules critically and therefore is believed to disrupt the axonal cytoskeleton and retrograde transport, with the subsequent decline in neuronal numbers and cognition (Iqbal & Grundke‐Iqbal, 1996). Cognitive impairment and a reduction in brain volume is also recognized as a clinical feature of schizophrenia (Pantelis et al ., 2003); however, this disorder does not appear to be associated with tau‐aggregate formation (Mukaetova‐Ladinska et al ., 2002).…”

Section: Introductionmentioning

confidence: 99%

Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain

Swatton

Sellers

Faull

et al. 2004

Eur J of Neuroscience

144

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Abnormal phosphorylation of tau is a feature of Alzheimer's disease (AD), which develops prematurely in Down syndrome (DS) patients. Cognitive impairment is also recognized as a clinical characteristic of schizophrenia, which does not appear to be associated with tau-aggregate formation. Several kinases can phosphorylate tau in cell-free assays. Here we show increased activity of mitogen-activated protein kinases (MAPKs) (including ERK1/2, SAPKs and p38) in post mortem AD and DS brains, which could not be accounted for by expression changes. In contrast, glycogen synthase kinase-3 activity (GSK-3 alpha beta) was reduced significantly. Examination of tau in AD and DS using antibodies selective for MAPK phosphorylation sites showed increased immunoreactivity. In addition, phosphorylation of S(199), reportedly a selective substrate for cyclin-dependent kinase-5 (cdk5) or GSK-3 alpha beta was only observed in AD samples, which showed a concomitant increase in the expression of p25, the enhancing cofactor for cdk5 activity. However, in schizophrenia brain, MAPK-phosphorylated tau was unchanged compared to matched controls, despite similar expression levels to those in AD. The activities of the MAPKs and GSK-3 alpha beta were also unchanged. These data demonstrate that in AD and DS, enhanced MAPK activity, which has an established role in regulating neuronal plasticity and survival, can account for irregular tau phosphorylation, and that the molecular processes involved in these neurodegenerative disorders are distinct from those in schizophrenia. These data also question the significance of GSK-3 alpha beta, as much previous work carried out in vitro has placed this kinase as a favoured candidate for involvement in the pathological phosphorylation of tau.

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Section: Introductionmentioning

confidence: 99%

Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain

Swatton

Sellers

Faull

et al. 2004

Eur J of Neuroscience

144

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“…Tau normally functions as a microtubule binding protein the role of which is to stabilize the microtubule network, providing for the transport of organelles and vesicles Forman et al, 2004;Skovronsky et al, 2006]. When identified ser/thr residues in or around the ''repeat domains'' of tau are hyperphosphorylated, the binding of tau to the microtubule becomes unstable [Gustke et al, 1994;Terry, 1996;Iqbal and Grundke-Iqbal, 1996;Preuss et al, 1997;Cho and Johnson, 2004;Lovestone et al, 1996;Wagner et al, 1996], and neuronal death may ensue via a breakdown in axonal transport. In support of this hypothesis, microtubule stabilization with taxol administered to a transgenic mouse model with hyperphosphorylated tau plus NFTs, restored fast axonal transport in spinal axons, and ameliorated motor impairments [Zhang et al, 2005].…”

Section: Tau Kinases Are a Primary Target For Kinase Inhibitor Develomentioning

confidence: 98%

Advances in the development of kinase inhibitor therapeutics for Alzheimer's disease

Savage

Gingrich²

2009

Drug Development Research

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Pharmaceutical approaches to slow the progression of Alzheimer's disease (AD) have focused primarily on reducing production or increasing clearance of amyloid b peptide (Ab Key words: Alzheimer; tau; cyclin-dependent kinase 5; CDK5; glycogen synthase kinase 3; GSK3; c-Jun N-terminal kinase; JNK; p38 kinase; Casein kinase 1; CK1; Rho kinase; Rock; p21-activating kinase; Pak AMYLOID AND TAU BRAIN PATHOLOGIES HAVE DIRECTED KINASE TARGET EFFORTSAlzheimer's disease (AD) is characterized by the accumulation in hippocampal and cortical brain regions of two insoluble, proteinaceous aggregates. The amyloid plaque is composed primarily of extraneuronal deposits of amyloid b (Ab), which is cleaved from the amyloid precursor protein (APP) by two intracellular proteases, b-and g-secretase [Selkoe, 1991;Sisodia and St George-Hyslop, 2002;Vetrivel and Thinakaran, 2006] (Fig. 1). a-Secretase cuts approximately in the middle of Ab after lysine-16, precluding its formation. The neurofibrillary tangle (NFT) is composed primarily of intraneuronal deposits of hyperphosphorylated tau protein (ptau) (Fig. 2) Iqbal and Grundke-Iqbal, 2006;Hyman et al., 2005], thought to result from an imbalance of kinase and phosphatase activity. Together, amyloid deposits and neurofibrillary tangles define the AD brain, yet, are not unique to AD [Askanas and Engel, 2007;Hutton, 2001]. How these insoluble proteins contribute to the inflammation, neuronal and synaptic loss and behavioral decline that is also characteristic of AD is unknown. These pathologies have directed drug discovery efforts to slow the progression of AD, with the goal of reducing levels of Ab and ptau. Animal model systems have been developed incorporating increased expression of APP and tau, and with these systems, upstream targets such as secretases and kinases have been studied. This review will focus on a number of protein kinase targets implicated in AD pathology and the DDR Published online in Wiley InterScience (www.interscience.wiley. com).

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“…The third postulated theory at the end of the past century was the tau-based hypothesis [10]. It is based on aberrant tau protein, a microtubule-associated protein that stabilizes the neuronal cytoskeleton, as the origin of AD pathology.…”

Section: Introductionmentioning

confidence: 99%

Glycogen Synthase Kinase 3 Inhibitors in the Next Horizon for Alzheimer′s Disease Treatment

Martı́nez

Gil

Pérez

2011

International Journal of Alzheimer's Disease

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Glycogen synthase kinase 3 (GSK-3), a proline/serine protein kinase ubiquitously expressed and involved in many cellular signaling pathways, plays a key role in the pathogenesis of Alzheimer's disease (AD) being probably the link between β-amyloid and tau pathology. A great effort has recently been done in the discovery and development of different new molecules, of synthetic and natural origin, able to inhibit this enzyme, and several kinetics mechanisms of binding have been described. The small molecule called tideglusib belonging to the thiadiazolidindione family is currently on phase IIb clinical trials for AD. The potential risks and benefits of this new kind of disease modifying drugs for the future therapy of AD are discussed in this paper.

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Molecular Mechanism of Alzheimer's Neurofibrillary Degeneration and Therapeutic Interventiona

Cited by 35 publications

References 21 publications

Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain

Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain

Advances in the development of kinase inhibitor therapeutics for Alzheimer's disease

Glycogen Synthase Kinase 3 Inhibitors in the Next Horizon for Alzheimer′s Disease Treatment

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