Mechanism of Tau-Induced Neurodegeneration in Alzheimer Disease and Related Tauopathies

Alonso, Alejandra; Li, Ben; Grundke‐Iqbal, Inge; Iqbal, Khalid

doi:10.2174/156720508785132307

Cited by 120 publications

(68 citation statements)

References 128 publications

(161 reference statements)

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“…81 Destabilization of microctubules through tau hyperphosphorylation distorts axonal transport and contributes to neuronal death in AD. 82 Such hyperphosphorylation is carried out by various kinases, i.e. cyclin-dependent kinase 5 (CDK5), glycogen synthase 3β (GSK3β), extracellular signal regulated kinase 2 (ERK2) and casein kinase 1 (CK1).…”

Section: Acs Chemical Neurosciencementioning

confidence: 99%

Stabilizers of Neuronal and Mitochondrial Calcium Cycling as a Strategy for Developing a Medicine for Alzheimer's Disease

Fernández‐Morales

Arranz-Tagarro

Calvo-Gallardo³

et al. 2012

ACS Chem. Neurosci.

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For the last two decades, most efforts on new drug development to treat Alzheimer's disease have been focused to inhibit the synthesis of amyloid beta (Aβ), to prevent Aβ deposition, or to clear up Aβ plaques from the brain of Alzheimer's disease (AD) patients. Other pathogenic mechanisms such as the hyperphosphorylation of the microtubular tau protein (that forms neurofibrillary tangles) have also been addressed as, for instance, with inhibitors of the enzyme glycogen synthase-3 kinase beta (GSK3β). However, in spite of their proven efficacy in animal models of AD, all these compounds have so far failed in clinical trials done in AD patients. It seems therefore desirable to explore new concepts and strategies in the field of drug development for AD. We analyze here our hypothesis that a trifunctional chemical entity acting on the L subtype of voltage-dependent Ca 2+ channels (VDCCs) and on the mitochondrial Na + /Ca 2+ exchanger (MNCX), and having additional antioxidant properties, may efficiently delay or stop the death of vulnerable neurons in the brain of AD patients. In recent years, evidence has accumulated indicating that enhanced neuronal Ca 2+ cycling (NCC) and futile mitochondrial Ca 2+ cycling (MCC) are central stage in activating calpain and calcineurin, as well as the intrinsic mitochondrial pathway for apoptosis, leading to death of vulnerable neurons. An additional contributing factor to neuronal death is the excess free radical production linked to distortion of Ca 2+ homeostasis. We propose that an hybrid compound containing a dihydropyridine moiety (to block L channels and mitigate Ca 2+ entry) and a benzothiazepine moiety (to block the MNCX and slow down the rate of Ca 2+ efflux from the mitochondrial matrix into the cytosol), as well as a polyphenol moiety (to sequester excess free radicals) could break down the pathological enhanced NCC and MCC, thus delaying the initiation of apoptosis and the death of vulnerable neurons. In so doing, such a trifunctional compound could eventually become a neuroprotective medicine capable of delaying disease progression in AD patients.

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Section: Acs Chemical Neurosciencementioning

confidence: 99%

Stabilizers of Neuronal and Mitochondrial Calcium Cycling as a Strategy for Developing a Medicine for Alzheimer's Disease

Fernández‐Morales

Arranz-Tagarro

Calvo-Gallardo³

et al. 2012

ACS Chem. Neurosci.

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“…All of these previous observations taken together suggested that hyperphosphorylation of Tau was a pivotal step in neurodegeneration and that the hyperphosphorylation probably induced a conformational change in the Tau molecule, which made it inhibitory and that the FTDP-17 mutant Tau acquired this gain of toxic function more readily (31).…”

mentioning

confidence: 94%

Phosphorylation of Tau at Thr212, Thr231, and Ser262 Combined Causes Neurodegeneration

Alonso

Clerico

et al. 2010

Journal of Biological Chemistry

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179

140

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Abnormal hyperphosphorylation of the microtubule-associated protein Tau is a hallmark of Alzheimer disease and related diseases called tauopathies. As yet, the exact mechanism by which this pathology causes neurodegeneration is not understood. The present study provides direct evidence that Tau abnormal hyperphosphorylation causes its aggregation, breakdown of the microtubule network, and cell death and identifies phosphorylation sites involved in neurotoxicity. We generated pseudophosphorylated Tau proteins by mutating Ser/Thr to Glu and, as controls, to Ala. These mutations involved one, two, or three pathological phosphorylation sites by site-directed mutagenesis using as backbones the wild type or FTDP-17 mutant R406W Tau. Pseudophosphorylated and corresponding control Tau proteins were expressed transiently in PC12 and CHO cells. We found that a single phosphorylation site alone had little influence on the biological activity of Tau, except Thr 212 , which, upon mutation to Glu in the R406W background, induced Tau aggregation in cells, suggesting phosphorylation at this site along with a modification on the C-terminal of the protein facilitates self-assembly of Tau. The expression of R406W Tau pseudophosphorylated at Thr 212 , Thr 231 , and Ser 262 triggered caspase-3 activation in as much as 85% of the transfected cells, whereas the corresponding value for wild type pseudophosphorylated Tau was 30%. Cells transfected with pseudophosphorylated Tau became TUNEL-positive.

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“…Microtubules are the "tracks" for axonal transport: disruption of the microtubules leads to compromised axoplasmic flow, dysfunction at the synaptic terminals, and eventually neuronal death. We have shown that hyperphosphorylation of tau is a pivotal event in the process of neurodegeneration: 1) abolish tau biological activity, 2) inhibits the microtubule assembly, 3) self-polymerizes into tangles of filaments, 4) dephosphorylation restores tau biological properties [1]. Here our objective is to verify our working hypothesis (Fig.…”

mentioning

confidence: 75%

Live Imaging, Immunocytochemistry and Electron Microscopic Studies of the Effect of Alzheimer-like Phosphorylation on Tau

2010

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Understanding mechanistically the foundation of synaptic withering and loss that precedes cell death in Alzheimer's disease (AD) and other neurodegenerative diseases is pivotal. Accumulation of hyperphosphorylated tau and the disruption of microtubules are correlated with synaptic loss and pathology of AD. One hallmark lesion of neurodegenerative disease in AD is the initial appearance of neurofibrillary tangles inside neurons. These tangles are composed mainly of hyperphosphorylated tau, a microtubule-associated protein (MAP), polymerized into paired helical and straight filaments (PHFs/SFs). Impaired cognitive function and pathology of AD is correlated with this lesion (PHFs/SFs). In in vitro assays, hyperphosphorylated tau is disruptive to microtubule assembly, whereas tau, stimulates tubulin assembly and subsequent stabilization of microtubules. Microtubules are disrupted in AD. Microtubules are the "tracks" for axonal transport: disruption of the microtubules leads to compromised axoplasmic flow, dysfunction at the synaptic terminals, and eventually neuronal death. We have shown that hyperphosphorylation of tau is a pivotal event in the process of neurodegeneration: 1) abolish tau biological activity, 2) inhibits the microtubule assembly, 3) self-polymerizes into tangles of filaments, 4) dephosphorylation restores tau biological properties [1]. Here our objective is to verify our working hypothesis (Fig. 1) of the involvement of tau phosphorylation toxic effect and study the influence of tau phosphorylation at Thr 212, Thr 231, and Ser 262 for tau-tau binding, self-assembly and the effect of its expression on the cells. Pseudophosphorylated tau was generated by site directed mutagenesis. Pseudophosphorylated tau was transiently expressed in PC12 cells, in CHO cells and in Porcine kidney epithelial cells (LLCPK) stably transfected for EB1-GFP (generously provided by Dr. Cassimeris [2]). The effect of expression of mutated taus on self assembly and binding to microtubules was studied by immunocytochemistry and by time-lapse microscopy. Caspase activation and apoptosis were determined by immunocytochemistry after transient transfection. For dynamic studies, we performed time-lapse fluorescent microscopy in two different systems: with fluorescent-tagged tau constructs that we generated and co-transfected in CHO cells with fluorescent-tagged tubulin and in the LLCPK cells transiently transfected with fluorescent tubulin and an inducible system for tau expression. We found that pseudophosphorylated tau aggregates in cells when Thr 212 is mutated to Glu, suggesting that phosphorylation at this site facilitates tau self-assembly. The expression of tau pseudophosphorylated at Thr212, Thr231, and Ser262 triggers caspase 3 activation in as much as 85% of the transfected cells and apoptosis to a lesser degree. These findings suggest that tau phosphorylation at Thr 212 facilitates tau selfaggregation, and that the combination of phosphorylation at Thr212, 231 and Ser262 in the same tau molecule can trigger toxic reacti...

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Mechanism of Tau-Induced Neurodegeneration in Alzheimer Disease and Related Tauopathies

Cited by 120 publications

References 128 publications

Stabilizers of Neuronal and Mitochondrial Calcium Cycling as a Strategy for Developing a Medicine for Alzheimer's Disease

Stabilizers of Neuronal and Mitochondrial Calcium Cycling as a Strategy for Developing a Medicine for Alzheimer's Disease

Phosphorylation of Tau at Thr212, Thr231, and Ser262 Combined Causes Neurodegeneration

Live Imaging, Immunocytochemistry and Electron Microscopic Studies of the Effect of Alzheimer-like Phosphorylation on Tau

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