Biomedical subjects

Khalid Iqbal

Publications and source records attributed to Khalid Iqbal.

At least 19 recordsLinked to original sources

PubMed2006

Regulation of phosphorylation of tau by protein kinases in rat brain.

Microtubule associated protein tau is abnormally hyperphosphorylated in Alzheimer disease (AD) brain. To investigate the role of protein kinases involved in this lesion, metabolically active slices made from brains of adult rats were treated with or without various specific kinase activators in oxygenated artificial cerebrospinal fluid. The basal kinase activities of protein kinase-A (PKA), CaM Kinase II and GSK-3 were stimulated more than two-fold by isoproterenol, bradykinin and wortmannin, respectively. We found that cdk5 activity was co-stimulated with PKA by isoproterenol. Sequential activation of PKA (+cdk5), CaM Kinase II and GSK-3 produced hyperphosphorylation of tau at Ser-198/Ser-199/Ser-202, Ser-214, Thr-231/Ser-235, Ser-262, Ser-396/Ser-404 and Ser-422 sites. Like AD P-tau, the P-tau from brain slices bound to normal tau and its binding to tubulin was inhibited. These studies suggest that PKA, cdk5, CaM Kinase II and GSK-3 are involved in the regulation of phosphorylation of tau and that AD-type phosphorylation of tau is probably a product of the synergistic action of two or more of these kinases.

Alzheimer Disease↗

PubMed2006

PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.

Phosphorylation of tau protein is regulated by several kinases, especially glycogen synthase kinase 3beta (GSK-3beta), cyclin-dependent protein kinase 5 (cdk5) and cAMP-dependent protein kinase (PKA). Phosphorylation of tau by PKA primes it for phosphorylation by GSK-3beta, but the site-specific modulation of GSK-3beta-catalyzed tau phosphorylation by the prephosphorylation has not been well investigated. Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. These studies reveal the nature of the inter-regulation of tau phosphorylation by the three major tau kinases.

Amino Acids↗

PubMed2006

Regulation of phosphorylation of tau by cyclin-dependent kinase 5 and glycogen synthase kinase-3 at substrate level.

Microtubule associated protein tau, which is expressed in six alternatively spliced molecular isoforms in human brain, is abnormally hyperphosphorylated in Alzheimer disease and related tauopathies. Here, we show (i) that GSK-3alpha and neither GSK-3beta nor cdk5 can phosphorylate tau at Ser262 and phosphorylation at Ser235 by cdk5 primes phosphorylation at Thr231 by GSK-3alpha/beta; (ii) that tau isoforms with two N-terminal inserts (tau4L, tau3L) are phosphorylated by cdk5 plus GSK-3 at Thr231 markedly more than isoforms lacking these inserts (tau4, tau3); and (iii) that Thr231 is phosphorylated approximately 50% more in free tau than in microtubule-bound tau, and the phosphorylation at this site results in the dissociation of tau from microtubules. These findings suggest that the phosphorylation of tau at Thr231 and Ser262 by cdk5 plus GSK-3, which inhibits its normal biological activity, is regulated both by its amino terminal inserts and its physical state.

Animals↗

PubMed2006

Role of a probiotic (Saccharomyces boulardii) in management and prevention of diarrhoea.

AIM: To assess the efficacy and safety of Saccharomyces boulardii (S. boulardii) in acute watery diarrhoea and its role in reducing the frequency of episodes of diarrhoea in subsequent two months. METHODS: Children from 2 mo to 12 years of age, with acute diarrhoea were selected according to inclusion criteria and randomised in S. boulardii group (treated with ORS, nutritional support and S. boulardii, 250 mg bid) and in control group (treated with ORS and nutritional support only). Active treatment phase was 5 d and each child was followed for two months afterwards. Frequency and consistency of stools as well as safety of drug was assessed on every visit. A comparison of two groups was done in terms of number of diarrhoeal episode in subsequent two months. RESULTS: There were fifty patients in each group. Baseline characteristics such as mean age and the average frequency of stools were comparable in S. boulardii and control group at the time of inclusion in the trial. By d 3 it reduced to 2.7 and 4.2 stools per d respectively and by d 6 it reduced to 1.6 (S. boulardii Group) and 3.3 (control group). The duration of diarrhoea was 3.6 d in S. boulardii group whereas it was 4.8 d in control group (P = 0.001). In the following two months, S. boulardii group had a significantly lower frequency of 0.54 episodes as compared to 1.08 episodes in control group. The drug was well accepted and tolerated. There were no reports of the side effects during treatment period. CONCLUSION: S. boulardii significantly reduces the frequency and duration of acute diarrhoea. The consistency of stool also improves. The drug is well-tolerated.

Child↗

PubMed2006

Trophic factors counteract elevated FGF-2-induced inhibition of adult neurogenesis.

The dentate gyrus of adult mammalian brain contains neural progenitor cells with self-renewal and multi-lineage potential. The lineage and maturation of the neural progenitors are determined by the composition and levels of the trophic factors in their microenvironment. In Alzheimer disease (AD) brain, especially the hippocampus, the level of basic fibroblast growth factor (FGF-2) is markedly elevated. Here we show that elevated FGF-2 enhances the division and nestin levels of cultured adult rat hippocampal progenitors but impairs neuronal lineage determination and maturation of these cells in culture. The trophic factors ciliary neurotrophic factor (CNTF), glial-derived neurotrophic factor (GDNF), and insulin-like growth factors-1 and -2 (IGF-1, IGF-2) as well as an Alzheimer peptidergic drug, Cerebrolysin((R)) (CL), in which we found these neurotrophic activities, counteract the effect of FGF-2 in inducing neuronal lineage (early neurogenesis). Whereas CNTF is the most active of the neurotrophic factors studied in promoting neurogenesis, CL, probably because of a combined effect of these factors, induces similar changes but without inhibiting cell proliferation. These findings suggest that CNTF, GDNF, IGF-1, and IGF-2 are promising therapeutic targets for AD and other diseases in which neurogenesis is probably inhibited.

Amino Acids↗

PubMed2006

Involvement of I2PP2A in the abnormal hyperphosphorylation of tau and its reversal by Memantine.

The activity of protein phosphatase (PP)-2A, which regulates tau phosphorylation, is compromised in Alzheimer disease brain. Here we show that the transient transfection of PC12 cells with inhibitor-2 (I2PP2A) of PP2A causes abnormal hyperphosphorylation of tau at Ser396/Ser404 and Ser262/Ser356. This hyperphosphorylation of tau is observed only when a sub-cellular shift of I2PP2A takes place from the nucleus to the cytoplasm and is accompanied by cleavage of I2PP2A into a 20 kDa fragment. Memantine, an un-competitive inhibitor of N-methyl-D-aspartate receptors, inhibits this abnormal phosphorylation of tau and cell death and prevents the I2PP2A-induced inhibition of PP2A activity in vitro. These findings demonstrate novel mechanisms by which I2PP2A regulates the intracellular activity of PP2A and phosphorylation of tau, and by which Memantine modulates PP2A signaling and inhibits neurofibrillary degeneration.

Animals↗

PubMed2006

Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity.

Accumulation of abnormally hyperphosphorylated tau (P-tau) in the form of tangles of paired helical filaments and/or straight filaments is one of the hallmarks of Alzheimer's disease (AD) and other tauopathies. P-tau is also found unpolymerized in AD. Although the cognitive decline is known to correlate with the degree of neurofibrillary pathology, whether the formation of filaments or the preceding abnormal hyperphosphorylation of tau is the inhibitory entity that leads to neurodegeneration has been elusive. We have previously shown that cytosolic abnormally hyperphosphorylated tau in AD brain (AD P-tau) sequesters normal tau (N-tau), microtubule-associated protein (MAP) 1, and MAP2, which results in the inhibition of microtubule assembly and disruption of microtubules. Here, we show that polymerization of AD P-tau into filaments inhibits its ability to bind N-tau and as well as the ability to inhibit the assembly of tubulin into microtubules in vitro and in the regenerating microtubule system from cultured cells. Like AD P-tau, the in vitro abnormally hyperphosphorylated recombinant brain N-tau binds N-tau and loses this binding activity on polymerization into filaments. Dissociation of the hyperphosphorylated N-tau filaments by ultrasonication restores its ability to bind N-tau. These findings suggest that the nonfibrillized P-tau is most likely the responsible entity for the disruption of microtubules in neurons in AD. The efforts in finding a therapeutic intervention for tau-induced neurodegeneration need to be directed either to prevent the abnormal hyperphosphorylation of this protein or to neutralize its binding to normal MAPs, rather than to prevent its aggregation into filaments.

3T3 Cells↗

PubMed2006

Assessments of the accumulation severities of amyloid beta-protein and hyperphosphorylated tau in the medial temporal cortex of control and Alzheimer's brains.

Alzheimer's disease (AD) is characterized neuropathologically by neuritic plaques (NPs), and neurofibrillary tangles (NFTs). So far, the following key issues are not yet answered to the disease: (1) the accumulation degrees of three Abeta variants, and tau phosphorylation epitopes in AD as compared to control; (2) the correlation degrees of levels of three Abeta variants with different tau phosphorylation epitopes; (3) the correlation degrees of levels of three Abeta variants and different tau phosphorylation epitopes with Braak and CERAD staging systems. To address these issues, levels of Abeta40, Abeta42, and Abeta43, and phosphorylated tau were assessed by dot blots in homogenates of the medial temporal cortex from AD and control brains in the present study. These data implied different roles of tau phosphorylation epitopes in formation of NFTs, and in this process, Abeta might play a key role. Assessments of levels of these abnormal proteins by dot blots may serve as a useful complement to the morphological evaluations in diagnosis of AD.

Aged↗

PubMed2006

Dysregulation of protein phosphorylation/dephosphorylation in Alzheimer's disease: a therapeutic target.

Studies during the last two decades have provided new insights into the molecular mechanism of Alzheimer's disease (AD). One of the milestone findings in AD research was the demonstration that neurofibrillary degeneration characterized by tau pathology is central to the pathogenesis of AD and other tauopathies and that abnormal hyperphosphorylation of tau is pivotal to neurofibrillary degeneration. This article reviews the recent research advances in tau pathology and the underlying dysregulation of the protein phosphorylation/dephosphorylation system. An updated model of the mechanism of neurofibrillary degeneration is also presented, and a promising therapeutic target to treat AD by correcting dysregulation of protein phosphorylation/dephosphorylation is discussed.

Journal Article↗

PubMed2006

From tau to toxicity: emerging roles of NMDA receptor in Alzheimer's disease.

Glutamate toxicity through NMDA receptor channels has long been central to the understanding of acute neuronal injury. Recent studies implicate similar events in chronic neurodegenerative diseases. Here, we analyze some of the most intriguing evidence for NMDA receptor-mediated cellular dysfunction and propose a mechanism by which hyperactive NMDA receptors might lead to neurofibrillary degeneration in Alzheimer's disease.

Activation Analysis↗

PubMed2006

Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation.

Neurofibrillary degeneration characterized by abnormal hyperphosphorylation and aggregation of tau in affected neurons is directly associated with dementia symptoms and plays a pivotal role in the pathogenesis of Alzheimer disease (AD) and related tauopathies. It is well established that brain glucose uptake/metabolism is impaired in AD, but how this impairment contributes to the disease is unknown. We recently found that tau in human brain is also modified by O-GlcNAcylation in addition to phosphorylation and that the former negatively regulates the latter. On the basis of these findings, we propose a novel hypothesis that the impaired glucose uptake/metabolism contributes to AD by facilitating abnormal hyperphosphorylation of tau. Further studies of this mechanism are likely to offer a novel therapeutic target for preventing and treating AD.

Acetylglucosaminidase↗

PubMed2006

Discoveries of tau, abnormally hyperphosphorylated tau and others of neurofibrillary degeneration: a personal historical perspective.

Alzheimer disease was described by Alois Alzheimer in 1907, but it was not until approximately 60-70 years later that any new significant developments were reported on the pathology of this disease. The discoveries that laid down the foundation for the exciting research that has been carried out during the last approximately 20 years and that have significantly enhanced our understanding of the disease are the ultrastructure of neurofibrillary tangles and neuritic (senile) plaques, the clinical-pathological correlation of these lesions to the presence of dementia, and the bulk isolation and protein composition of paired helical filaments and plaque amyloid. We discovered tau as the major protein subunit of paired helical filaments/neurofibrillary tangles, the abnormal hyperphosphorylation of this protein in this lesion and in Alzheimer brain cytosol and the gain of toxic function by the cytosolic abnormally hyperphosphorylated tau in Alzheimer brain. Here we present a personal historical account of the work in our laboratories that led, in 1986, to the discoveries of tau and its abnormal hyperphosphorylation in paired helical filaments and Alzheimer brain cytosol. This article also describes several major findings which subsequently resulted from the abnormal hyperphosphorylation of tau and in a large part account for the current understanding of the role of this lesion in Alzheimer disease and other tauopathies.

Aged↗

PubMed2005

Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain.

A disturbance of calcium homeostasis is believed to play an important role in the neurodegeneration of the brains of Alzheimer disease (AD) patients, but the molecular pathways by which it contributes to the disease are not well understood. Here we studied the activation of two major Ca(2+)-regulated brain proteins, calpain and calcineurin, in AD brain. We found that calpain I is activated, which in turn cleaves and activates calcineurin in AD brain. Mass spectrometric analysis indicated that the cleavage of calcineurin by calpain I is at lysine 501, a position C-terminal to the autoinhibitory domain, which produces a 57-kDa truncated form. The 57-kDa calcineurin maintains its Ca(2+)/calmodulin dependence of the phosphatase activity, but the phosphatase activity is remarkably activated upon truncation. The cleavage and activation of calcineurin correlate to the number of neurofibrillary tangles in human brains. These findings suggest that the overactivation of calpain I and calcineurin may mediate the role of calcium homeostatic disturbance in the neurodegeneration of AD.

Aged↗

PubMed2005

Inhibitors of protein phosphatase-2A from human brain structures, immunocytological localization and activities towards dephosphorylation of the Alzheimer type hyperphosphorylated tau.

Protein phosphatase (PP)-2A, which regulates the phosphorylation of tau, is regulated by two endogenous inhibitor proteins, I(1)(PP2A) and I(2)(PP2A), in mammalian tissues. Here, we report the cloning of I(1)(PP2A) and I(2)(PP2A) from human brain, and show that in PC12 cells and in I(1)(PP2A)-GFP or I(2)(PP2A)-GFP transfected NIH3T3 and human neural progenitor cells, I(1)(PP2A) is localized mostly in the cell cytoplasm and I(2)(PP2A) mostly in the nucleus. The recombinant I(1)(PP-2A) and I(2)(PP-2A) inhibit PP-2A activity towards hyperphosphorylated tau in vitro; the dephosphorylation of the hyperphosphorylated tau at specific sites is selectively inhibited. Overexpression of I(1)(PP2A) as well as I(2)(PP2A) results in tau hyperphosphorylation and degeneration of PC 12 cells.

Alzheimer Disease↗

PubMed2005

Metabolic/signal transduction hypothesis of Alzheimer's disease and other tauopathies.

Alzheimer's disease (AD), the major cause of dementia in middle- to old-aged individuals, is multifactorial. Independent of the etiology, whether genetic or non-genetic, this disease is characterized by extracellular beta-amyloid plaques and intraneuronal neurofibrillary tangles of abnormally hyperphosphorylated tau. However, the molecular mechanisms of neither AD nor other tauopathies are completely understood. To date, the most popular hypothesis of AD is the "Amyloid cascade hypothesis", according to which beta-amyloid, the cleavage product of beta-amyloid precursor protein (APP), is neurotoxic and causes neurodegeneration and dementia. However, this hypothesis is inconsistent with the presence in normal aged human brain of the beta-amyloid plaque burden similar to that in AD, and the absence of neurofibrillary pathology and neurodegeneration in mutated APP, presenilin-1 and presenilin-2 transgenic mice that show extensive beta-amyloid plaque pathology. Here we propose an alternate hypothesis, the "Metabolic/signal transduction hypothesis", which is consistent both with the pathology seen in AD and other tauopathies and as well as all experimental animal conditions. In this hypothesis, with increasing age, the fluidity of neuronal membranes is progressively reduced, which makes it less resistant to environmental/metabolic insults affecting one or more signal transduction pathways, which lead to a protein phosphorylation/dephosphorylation imbalance and abnormal hyperphosphorylation of tau. The hyperphosphorylated tau sequesters normal tau, MAP1 and MAP2, which results in breakdown of the microtubule network and, consequently, a progressive retrograde degeneration of the affected neurons and, ultimately, dementia.

Alzheimer Disease↗

PubMed2005

NF-kappaB precursor, p105, and NF-kappaB inhibitor, IkappaBgamma, are both elevated in Alzheimer disease brain.

The nuclear factor-kappaB (NF-kappaB) signal transduction pathway regulates several vital cellular processes. During our studies of the glycoproteins involved in Alzheimer disease (AD), we found a significant increase of a 45-kDa protein band that was stained by lectin Maackia amurensis agglutinin (MAA). Mass spectrometry and Western blot analyses indicated that this 45-kDa MMA-positive protein was an inhibitor of NF-kappaB, IkappaBgamma. By Western blot analysis, the levels of both IkappaBgamma and NF-kappaB precursor, p105, were found to be elevated in AD brain as compared to age-matched controls. Our findings suggest that the NF-kappaB pathway might be involved in the molecular mechanism of AD.

Aged↗

PubMed2005

Tau pathology in Alzheimer disease and other tauopathies.

Just as neuronal activity is essential to normal brain function, microtubule-associated protein tau appears to be critical to normal neuronal activity in the mammalian brain, especially in the evolutionary most advanced species, the homo sapiens. While the loss of functional tau can be compensated by the other two neuronal microtubule-associated proteins, MAP1A/MAP1B and MAP2, it is the dysfunctional, i.e., the toxic tau, which forces an affected neuron in a long and losing battle resulting in a slow but progressive retrograde neurodegeneration. It is this pathology which is characteristic of Alzheimer disease (AD) and other tauopathies. To date, the most established and the most compelling cause of dysfunctional tau in AD and other tauopathies is the abnormal hyperphosphorylation of tau. The abnormal hyperphosphorylation not only results in the loss of tau function of promoting assembly and stabilizing microtubules but also in a gain of a toxic function whereby the pathological tau sequesters normal tau, MAP1A/MAP1B and MAP2, and causes inhibition and disruption of microtubules. This toxic gain of function of the pathological tau appears to be solely due to its abnormal hyperphosphorylation because dephosphorylation converts it functionally into a normal-like state. The affected neurons battle the toxic tau both by continually synthesizing new normal tau and as well as by packaging the abnormally hyperphosphorylated tau into inert polymers, i.e., neurofibrillary tangles of paired helical filaments, twisted ribbons and straight filaments. Slowly but progressively, the affected neurons undergo a retrograde degeneration. The hyperphosphorylation of tau results both from an imbalance between the activities of tau kinases and tau phosphatases and as well as changes in tau's conformation which affect its interaction with these enzymes. A decrease in the activity of protein phosphatase-2A (PP-2A) in AD brain and certain missense mutations seen in frontotemporal dementia promotes the abnormal hyperphosphorylation of tau. Inhibition of this tau abnormality is one of the most promising therapeutic approaches to AD and other tauopathies.

Alzheimer Disease↗

PubMed2005

Bilateral injection of isoproterenol into hippocampus induces Alzheimer-like hyperphosphorylation of tau and spatial memory deficit in rat.

The abnormal hyperphosphorylation of tau protein is one of the hallmarks of Alzheimer disease and other tauopathies; as yet the exact role of various tau kinases in this pathology is not fully understood. Here, we show that injection of isoproterenol, an activator of cAMP-dependent kinase (PKA), into rat hippocampus bilaterally results in the activation of PKA, calcium/calmodulin-dependent kinase II and cyclin-dependent kinase-5, inhibition of protein phosphatase-2A, hyperphosphorylation of tau at several Alzheimer-like epitopes and a disturbance of spatial memory retention 48 h after the drug injection. These findings suggest the involvement of PKA and PKA-mediated signaling pathway in the Alzheimer-like tau hyperphosphorylation and memory impairment.

Alzheimer Disease↗