1.
WW domain-containing oxidoreductase promotes neuronal differentiation via negative regulation of glycogen synthase kinase 3β
Source
Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan, Taiwan.
Abstract
WW domain-containing oxidoreductase (WWOX), a putative tumour suppressor, is suggested to be involved in the hyperphosphorylation of Alzheimer's Tau. Tau is a microtubule-associated protein that has an important role in microtubule assembly and stability. Glycogen synthase kinase 3β (GSK3β) has a vital role in Tau hyperphosphorylation at its microtubule-binding domains. Hyperphosphorylated Tau has a low affinity for microtubules, thus disrupting microtubule stability. Bioinformatics analysis indicated that WWOX contains two potential GSK3β-binding FXXXLI/VXRLE motifs. Immunofluorescence, immunoprecipitation and molecular modelling showed that WWOX interacts physically with GSK3β. We demonstrated biochemically that WWOX can bind directly to GSK3β through its short-chain alcohol dehydrogenase/reductase domain. Moreover, the overexpression of WWOX inhibited GSK3β-stimulated S396 and S404 phosphorylation within the microtubule domains of Tau, indicating that WWOX is involved in regulating GSK3β activity in cells. WWOX repressed GSK3β activity, restored the microtubule assembly activity of Tau and promoted neurite outgrowth in SH-SY5Y cells. Conversely, RNAi-mediated knockdown of WWOX in retinoic acid (RA)-differentiated SH-SY5Y cells inhibited neurite outgrowth. These results suggest that WWOX is likely to be involved in regulating GSK3β activity, reducing the level of phosphorylated Tau, and subsequently promoting neurite outgrowth during neuron differentiation. In summary, our data reveal a novel mechanism by which WWOX promotes neuronal differentiation in response to RA.Cell Death and Differentiation advance online publication, 23 December 2011; doi:10.1038/cdd.2011.188.
Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer's disease.
Source
Departments of Pathology, Neurosurgery, Neurology, and Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.
Abstract
Alzheimer's disease (AD) is the most common cause of dementia in North America. Growing evidence supports the concept that AD is fundamentally a metabolic disease that results in progressive impairment in the brain's capacity to utilize glucose and respond to insulin and insulin-like growth factor (IGF) stimulation. Moreover, the heterogeneous nature of AD is only partly explained by the brain's propensity to accumulate aberrantly processed, misfolded and aggregated oligomeric structural proteins, including amyloid-β peptides and hyperphosphorylated tau. Evidence suggests that other factors, including impaired energy metabolism, oxidative stress, neuroinflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into an overarching hypothesis to develop more realistic diagnostic and therapeutic approaches to AD. In this review, the interrelationship between impaired insulin and IGF signalling and amyloid-β pathology is discussed along with potential therapeutic approaches. Impairments in brain insulin/IGF signalling lead to increased expression of amyloid-β precursor protein (AβPP) and accumulation of AβPP-Aβ. In addition, they promote oxidative stress and deficits in energy metabolism, leading to the activation of pro-AβPP-Aβ-mediated neurodegeneration cascades. Although brain insulin/IGF resistance and deficiency can be induced by primary or secondary disease processes, the soaring rates of peripheral insulin resistance associated with obesity, diabetes mellitus and metabolic syndrome quite likely play major roles in the current AD epidemic. Both clinical and experimental data have linked chronic hyperinsulinaemia to cognitive impairment and neurodegeneration with increased AβPP-Aβ accumulation/reduced clearance in the CNS. Correspondingly, both the restoration of insulin responsiveness and the use of insulin therapy can lead to improved cognitive performance, although with variable effects on brain AβPP-Aβ load. On the other hand, experimental evidence supports the concept that the toxic effects of AβPP-Aβ can promote insulin resistance. Together, these findings suggest that a positive feedback loop of progressive neurodegeneration can develop whereby insulin resistance drives AβPP-Aβ accumulation, and AβPP-Aβ fibril toxicity drives brain insulin resistance. This phenomenon could explain why measuring AβPP-Aβ levels in cerebrospinal fluid or imaging of the brain has proven to be inadequate as a stand-alone biomarker for diagnosing AD, and why the clinical trial results of anti-AβPP-Aβ monotherapy have been disappointing. Instead, the aggregate data suggest that brain insulin resistance and deficiency must also be therapeutically targeted to halt AD progression or reverse its natural course. The positive therapeutic effects of different treatments that address the role of brain insulin/IGF resistance and deficiency, including the use of intranasal insulin delivery, incretins and insulin sensitizer agents are discussed along with potential benefits of lifestyle changes to modify risk for developing mild cognitive impairment or AD. Altogether, the data strongly support the notion that we must shift toward the implementation of multimodal rather than unimodal diagnostic and therapeutic strategies for AD.
Endoplasmic reticulum stress: a new playER in tauopathies.
Source
Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
Abstract
The accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER) activates the unfolded protein response (UPR), which involves a set of protein signalling pathways and transcription factors that re-establish homeostasis and normal ER function, adapting cells to ER stress. If this adaptive response is insufficient, the UPR triggers an apoptotic program to eliminate irreversibly damaged cells. Recent observations suggest that ER stress plays an important role in the pathogenesis of various neurodegenerative disorders such as Alzheimer's disease, which is characterized by the deposition of amyloid-beta (Abeta) and hyperphosphorylated tau in susceptible brain regions. Moreover, several studies demonstrate that Abeta induces UPR activation, which in turn promotes tau phosphorylation. In the study by Nijholt and colleagues, reported in the current issue of The Journal of Pathology, the association between UPR activation and tau pathology was investigated in the brain of patients diagnosed with sporadic or familial tauopathies in which Abeta deposits are absent. The authors described that increased levels of UPR activation markers are predominantly observed in neurons within the hippocampus, being correlated with early tau phosphorylation. These findings suggest that UPR activation, which occurs in an Abeta-independent manner, is an early event during taupathology and point to a functional crosstalk between these molecular mechanisms in tauopathies. A better understanding of UPR activation in tauopathies can thus contribute to the design of new therapeutic strategies with the purpose of promoting neuronal cell survival in these disorders. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Propyl isomerase Pin1 promotes APP protein turnover by inhibiting GSK3β kinase activity: A novel mechanism for Pin1 to protect against Alzheimer's disease.
Source
Beth Israel Deaconese Medical Center, United States;
Abstract
Alzheimer's disease (AD) is characterized by the presence of senile plaques of amyloid-beta peptides (Aβ) derived from amyloid precursor protein (APP) and neurofibrillary tangles composed of hyperphosphorylated tau. Increasing APP gene dosage or expression has been shown to cause familial early-onset AD. However, whether protein stability of APP is regulated is unclear. The prolyl isomerase Pin1 and glycogen synthase 3β (GSK3β) have been shown to have the opposite effects on APP processing and tau hyperphosphorylation, relevant to the pathogenesis of AD. However, nothing is known about their relationship. In this study, we found that Pin1 binds to the pT330-P motif in GSK3β to inhibit its kinase activity. Furthermore, Pin1 promotes protein turnover of APP by inhibiting GSK3β activity. A point mutation either at T330, the Pin1-binding site in GSK3β, or T668, the GSK3β phosphorylation site in APP, abolished the regulation of GSK3β activity, T668 phosphorylation and APP stability by Pin1, resulting in reduced non-amyloidogenic APP processing and increased APP levels. These results uncover a novel role of Pin1 in inhibiting GSK3β kinase activity to reduce APP protein levels, providing a previously unrecognized mechanism by which Pin1 protects against Alzheimer's disease.
Effect of chronic administration of estradiol, progesterone, and tibolone on the expression and phosphorylation of glycogen synthase kinase-3β and the microtubule-associated protein tau in the hippocampus and cerebellum of female rat.
Source
Unidad de Investigación Médica en Farmacología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México D.F., México.
Abstract
Gonadal hormones regulate expression and activation of protein tau. Tibolone is a drug used as first- choice comprehensive treatment for the relief of menopausal symptoms, because it and its various metabolites have estrogenic properties and progestogenic/androgenic effects; however, the effect on the activation of tau protein and its signaling cascade in the brain is unknown. We studied the effect of chronic administration of estradiol (E2), progesterone (P4), and tibolone (TIB) on the expression and phosphorylation of microtubule-associated protein tau and glycogen synthase kinase-3β (GSK3β) in the hippocampus and cerebellum of ovariectomized rats. Ovariectomized adult female rats were implanted with pellets of vehicle, E2, or P4 or were treated with TIB by oral administration for 60 days. The animals were sacrificed, and tissue proteins were analyzed by Western blot. We observed that, in the hippocampus, administration of E2, P4, or TIB significantly decreased the protein content of hyperphosphorylated tau and increased the taudephosphorylated form, whereas only treatment with TIB increased the content of the phosphorylated form of GSK3β. In the cerebellum, E2 and TIB treatments resulted in a significant decrease in the expression of hyperphosphorylated tau, whereas E2 and TIB increased phosphorylated GSK3β; P4 had no effect. These results indicate that chronic administration of gonadal hormones and tibolone modulates tau and GSK3β phosphorylation in hippocampus and cerebellum of the rat and may exert a neuroprotective effect in these tissues. © 2011 Wiley Periodicals, Inc.
Copyright © 2011 Wiley Periodicals, Inc.
Hyperphosphorylated tau in young and middle-aged subjects.
Source
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University/Uppsala University Hospital, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden.
Abstract
The brain tissue obtained from ninety-five cognitively unimpaired subjects, with ages ranging from 22 to 50 years upon death, were immunohistochemically assessed for neurodegenerative changes, i.e., hyperphosphorylated tau (HPτ) and β-amyloid (Aβ) pathology in predilection neuroanatomical areas. HPτ pathology was observed in the transentorhinal cortex and/or the locus coeruleus (LC) in 33% of the subjects, without any obvious risk factors known to alter the microtubule-associated protein. HPτ pathology was noted in the LC in 25 out of 83 subjects (30%), lacking concomitant cortical Aβ or transentorhinal HPτ pathology. This observation was present even when assessing only one routine section of 7 μm thickness. The recent suggestion of prion-like propagation of neurodegeneration and the finding of neurodegeneration being quite common in middle-aged persons is alarming. It is noteworthy, however, that a substantial number of neurologically unimpaired subjects even at a very old age display only sparse to modest extent of neurodegenerative pathology. Thus, only a subset of subjects with neurodegenerative changes early in life seem to progress to a symptomatic disease with ageing. This observation brings forth the notion that other, yet unknown modifying factors influence the progression of degeneration that leads to a symptomatic disorder. The known association between alterations in the LC and mood disorders, and the finding of the LC being frequently affected with HPτ pathology suggest that clinicopathological studies on young subjects both with or without mood disorders are warranted.
Enriched odor exposure decrease tau phosphorylation in the rat hippocampus and cortex.
Source
Department of Pathophysiology, Key Laboratory of Neurological Diseases of Education Committee of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
Abstract
Abnormally hyperphosphorylated microtubule-associated protein tau is the main component of the neurofibrillary tangles (NFT), a hallmark pathological feature of Alzheimer's disease (AD). A lot of studies suggested that there is highly neurobiological correlation between olfactory dysfunction and AD-like pathology, but the effect of the odor stimulation ontau phosphorylation remains unknown. Here, we examined the effect of short-term and long-term enriched odor exposure on the alterations of tau phosphorylation at multiple sites in the rat brains. We found that short-term odor enrichment did not affect the phosphorylation of tau, while long-term odor enrichment dramatically reduce the phosphorylation level oftau at Ser198/199/202, Thr231, Ser396, and Ser404 sites both in the hippocampus and cortex. These data suggest that long-term odor exposure prevent tau phosphorylation and may be a new therapeutic strategy of AD.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer's disease.
Source
Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland; Department of Neurology, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland.
Abstract
The p62/sequestosome-1 is a multifunctional protein containing several protein-protein interaction domains. Through these interactions p62 is involved in the regulation of cellular signaling and protein trafficking, aggregation and degradation. p62 protein can bind through its UBA motif to ubiquitinated proteins and control their aggregation and degradation via either autophagy or proteasomes. p62 protein has been reported to be seen in association with the intracellular inclusions in primary and secondary tauopathies, α-synucleinopathies and other neurodegenerative brain disorders displaying inclusions with misfolded proteins. In Alzheimer's disease (AD), p62 protein is associated with neurofibrillary tangles composed primarily of hyperphosphorylated tau protein and ubiquitin. Increasing evidence indicates that p62 has an important role in the degradation of tau protein. The lack of p62 protein expression provokes the tau pathology in mice. Recent studies have demonstrated that the p62 gene expression and cytoplasmic p62 proteinlevels are significantly reduced in the frontal cortex of AD patients. Decline in the level of p62 protein can disturb the signaling pathways of Nrf2, cyclic AMP and NF-κB and in that way increase oxidative stress and impair neuronal survival. We will review here the molecular and functional characteristics of p62 protein and outline its potential role in the regulation of Alzheimer's pathogenesis.
Copyright © 2011 Elsevier Ltd. All rights reserved.
CEREBRAL Aβ(42) DEPOSITS AND MICROVASCULAR PATHOLOGY IN AGEING BABOONS.
Source
Institute of Primate Research, National Museums of Kenya, Nairobi, Kenya; Paul Flechsig Institute for Brain Research, University of Leipzig, Germany; Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; Institute for Ageing and Health, Newcastle University, NE4 5PL, UK.
Abstract
Background: Previous studies have extensively reported the deposition of amyloid β (Aβ) peptide with carboxyl- and amino-terminal heterogeneity in cortical and cerebrovascular deposits in Alzheimer's disease (AD) and in non-human primates except baboons. Methods: We examined the immunocytochemical distribution of Aβ peptides and Aβ oligomers in brain tissue from three subspecies of 18-28 year old baboons (Papio) and in other monkeys including the squirrel (Saimiri sciureus) and rhesus (Macaca mulatta) for comparison. Results: A general preponderance of Aβ(42) in parenchymal deposits and many vascular deposits in all cortical lobes was evident in the baboons. Aβοligomeric immunoreactivity was also apparent like to amyloid plaques. We found that the amino acid sequence of the Aβ domain of the baboon amyloid precursor protein is similar to that of man. In contrast to Aβ, immunoreactivity tohyperphosphorylated tau protein was largely intracellular and rare in these baboons. Brain tissues from squirrel and rhesus monkeys examined in parallel exhibited mostly vascular and parenchymal deposits containing Aβ(42) peptides. Our results were comparable to AD, but showed that even in younger monkeys exhibiting few deposits, Aβ(42) was evident in both parenchymal deposits and cerebral amyloid angiopathy. Perivascular amyloid deposits were frequent and often accompanied by microvascular abnormalities in the form of collapsed degenerated capillaries. Conclusions: Similar to other primates above and below in the phylogenetic order, our observations and evaluation of the literature implicate pathogenicity of Aβ(42) peptide associated with microvascular degeneration in baboons. We suggest baboons are useful animals to investigate the dynamics of AD-related pathology.
© 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society.
Interaction between α-Synuclein and Other Proteins in Neurodegenerative Disorders.
Source
Institute of Clinical Neurobiology, Kenyongasse 18, A-1070 Vienna, Austria.
Abstract
Protein aggregation is a common characteristic of many neurodegenerative disorders, and the interaction between pathological/toxic proteins to cause neurodegeneration is a hot topic of current neuroscience research. Despite clinical, genetic, and experimental differences, evidence increasingly indicates considerable overlap between synucleinopathies and tauopathies or other protein-misfolding diseases. Inclusions, characteristics of these disorders, also occurring in other neurodegenerative diseases, suggest interactions of pathological proteins engaging common downstream pathways. Novel findings that have shifted our understanding in the role of pathologic proteins in the pathogenesis of Parkinson and Alzheimer diseases have confirmed correlations/overlaps between these and other neurodegenerative disorders. The synergistic effects of α-synuclein, hyperphosphorylated tau, amyloid-β, and other pathologic proteins, and the underlying molecular pathogenic mechanisms, including induction and spread of protein aggregates, are critically reviewed, suggesting a dualism or triad of neurodegeneration in protein-misfolding disorders, although the etiology of most of these processes is still mysterious.
The Interface between Cytoskeletal Aberrations and Mitochondrial Dysfunction in Alzheimer's Disease and Related Disorders.
Source
Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Abstract
The major defining pathological hallmarks of Alzheimer's disease (AD) are the accumulations of Aβ in senile plaques and hyperphosphorylated tau in neurofibrillary tangles and neuropil threads. Recent studies indicate that rather than these insoluble lesions, the soluble Aβ oligomers and hyperphosphorylated tau are the toxic agents of AD pathology. Such pathological protein species are accompanied by cytoskeletal changes, mitochondrial dysfunction, Ca(2+) dysregulation, and oxidative stress. In this review, we discuss how the binding of Aβ to various integrins, defects in downstream focal adhesion signaling, and activation of cofilin can impact mitochondrial dysfunction, cytoskeletal changes, and tau pathology induced by Aβ oligomers. Such pathological consequences can also feedback to further activate cofilin to promote cofilin pathology. We also suggest that the mechanism of Aβ generation by the endocytosis of APP is mechanistically linked with perturbations in integrin-based focal adhesion signaling, as APP, LRP, and β-integrins are physically associated with each other.
Defects in the medial entorhinal cortex and dentate gyrus in the mouse model of Sanfilippo syndrome type B.
Source
Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
Abstract
Sanfilippo syndrome type B (MPS IIIB) is characterized by profound mental retardation in childhood, dementia and death in late adolescence; it is caused by deficiency of α-N-acetylglucosaminidase and resulting lysosomal storage of heparan sulfate. A mouse model, generated by homologous recombination of the Naglu gene, was used to study pathological changes in the brain. We found earlier that neurons in the medial entorhinal cortex (MEC) and the dentate gyrus showed a number of secondary defects, including the presence of hyperphosphorylated tau (Ptau) detected with antibodies raised against Ptau in Alzheimer disease brain. By further use of immunohistochemistry, we now show staining in neurons of the same area for beta amyloid, extending the resemblance to Alzheimer disease. Ptau inclusions in the dentate gyrus of MPS IIIB mice were reduced in number when the mice were administered LiCl, a specific inhibitor of Gsk3β. Additional proteins found elevated in MEC include proteins involved in autophagy and the heparan sulfate proteoglycans, glypicans 1 and 5, the latter closely related to the primary defect. The level of secondary accumulations was associated with elevation of glypican, as seen by comparing brains of mice at different ages or with different mucopolysaccharide storage diseases. The MEC of an MPS IIIA mouse had the same intense immunostaining for glypican 1 and other markers as MPS IIIB, while MEC of MPS I and MPS II mice had weak staining, and MEC of an MPS VI mouse had no staining at all for the same proteins. A considerable amount of glypican was found in MEC of MPS IIIB mice outside of lysosomes. We propose that it is the extralysosomal glypican that would be harmful to neurons, because its heparan sulfate branches could potentiate the formation of Ptau and beta amyloid aggregates, which would be toxic as well as difficult to degrade.
Long-term consequences of repetitive brain trauma: chronic traumatic encephalopathy.
Source
Center for Study of Traumatic Encephalopathy, Boston University School of Medicine, Boston University, 72 East Concord St, 7380, Boston, MA 02118, USA. bobstern@bu.edu
Abstract
Chronic traumatic encephalopathy (CTE) has been linked to participation in contact sports such as boxing and American football. CTE results in a progressive decline of memory and cognition, as well as depression, suicidal behavior, poor impulse control, aggressiveness, parkinsonism, and, eventually, dementia. In some individuals, it is associated with motor neuron disease, referred to as chronic traumatic encephalomyelopathy, which appears clinically similar to amyotrophic lateral sclerosis. Results of neuropathologic research has shown that CTE may be more common in former contact sports athletes than previously believed. It is believed that repetitive brain trauma, with or possibly without symptomatic concussion, is responsible for neurodegenerative changes highlighted by accumulations ofhyperphosphorylated tau and TDP-43 proteins. Given the millions of youth, high school, collegiate, and professional athletes participating in contact sports that involve repetitive brain trauma, as well as military personnel exposed to repeated brain trauma from blast and other injuries in the military, CTE represents an important public health issue. Focused and intensive study of the risk factors and in vivo diagnosis of CTE will potentially allow for methods to prevent and treat these diseases. Research also will provide policy makers with the scientific knowledge to make appropriate guidelines regarding the prevention and treatment of brain trauma in all levels of athletic involvement as well as the military theater.
Copyright © 2011 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.
GSPE interferes with tau aggregation in vivo: implication for treating tauopathy.
Source
Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA; Alzheimer Disease Research Unit, CIEN Foundation, Queen Sofia Foundation, Madrid, Spain.
Abstract
Tauopathies are characterized by progressive neurodegeneration caused by intracellular accumulation ofhyperphosphorylated tau protein aggregates in the brain. The present study was designed to test whether a grape seed polyphenolic extract (GSPE) previously shown to inhibit tau protein aggregation in vitro could benefit tau-mediated neuropathology and behavior deficits in JNPL3 transgenic mice expressing a human tau protein containing the P301L mutation. Nine-month-old JNPL3 mice were treated with GSPE delivered through their drinking water for 6 months. We found that GSPE treatment significantly reduced the number of motor neurons immunoreactive for hyperphosphorylatedand conformationally-modified tau in the ventral horns of the spinal cord identified using AT100, PHF-1, AT8, and Alz50tau antibodies. This coincided with a drastically reduced level of hyperphosphorylated and sarcosyl-insoluble tau in spinal cord fractions. Furthermore, the reduction of tau pathology was accompanied by an improvement in the motor function assessed by a wire hang test. Collectively, our results suggest that GSPE can interfere with tau-mediated neurodegenerative mechanisms and ameliorate neurodegenerative phenotype in an animal model of tauopathy. Our studies support further evaluation of GSPE for preventing and/or treating of tauopathies in humans.
Copyright © 2011 Elsevier Inc. All rights reserved.
Multi-target-directed ligands in Alzheimer's disease treatment.
Source
Jagiellonian University, Medical College, Chair of Pharmaceutical Chemistry, Department of Physicochemical Drug Analysis, 30-688 Kraków, Medyczna 9, Poland. mfmalaws@cyf-kr.edu.pl.
Abstract
Among the various drug discovery methods, a very promising modern approach consists in designing multi-target-directed ligands (MTDLs). This methodology has been specifically developed for treatment of disorders with complex pathological mechanisms. One such disorder is Alzheimer's disease (AD), currently the most common multifactorial neurodegenerative disease. AD is related to increased levels of the amyloid β peptide (Aβ) and the hyperphosphorylatedtau protein, along with loss of neurons and synapses. Moreover, there is some evidence pointing to the role of oxidative stress, metal ion deregulation, inflammation and cell cycle regulatory failure in its pathogenesis. There are many attractive targets for the development of anti-AD drugs, and the multi-factor nature of this disease calls for multi-target-directed compounds which can be beneficial for AD treatment. This review presents the discovery of dualand multi-acting anti-AD drug candidates, focusing on the novel design strategy and the compounds it yields - particularly hybrids obtained by linking structurally active moieties interacting with different targets. The first group of compounds includes cholinesterase inhibitors acting as dual binding site inhibitors and/or inhibitors with additional properties. These compounds are characterized by increased potency against acetylcholinesterase (AChE) and Aβ plaque formation with additional properties such as antioxidant activity, neuroprotective, and metal-complexing property, voltage-dependent calcium channel antagonistic activity, inhibitory activity against glutamate-induced excitotoxicity, histamine H(3) receptor antagonism, cannabinoid CB(1) receptor antagonism and β-secretase (BACE1) inhibition. A novel class of compounds represents the combination of dual BACE1 inhibitors with metal chelators, and dual modulators of γ-secretase with peroxisome proliferator-ativated receptor γ (PPARγ). We have reviewed the latest reports (2008-2011) presenting new multi-target-directed compounds in Alzheimer's disease treatment.
Transglutaminase 1 and its regulator tazarotene-induced gene 3 localize to neuronal tau inclusions in tauopathies.
Source
Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, The Netherlands. m.wilhelmus@vumc.nl.
Abstract
Alzheimer's disease (AD), progressive supranuclear palsy (PSP), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and Pick's disease (PiD) are commonly known as tauopathies. Neurodegeneration observed in these diseases is linked to neuronal fibrillary hyperphosphorylated tau protein inclusions. Transglutaminases (TGs) are inducible enzymes, capable of modifying conformational and/or structural properties of proteins by inducing molecular cross-links. Both transglutaminase 1 (TG1) and transglutaminase 2 (TG2) are abundantly expressed in the brain and are associated with fibrillary hyperphosphorylated tau protein inclusions in neurons of AD, so-called neurofibrillary tangles (NFTs). However, other data obtained by our group suggested that tau pathology in the brain may be primarily related to TG1 and not to TG2 activity. To obtain more information on this issue, we set out to investigate the association of TG1, TG2, and TG-catalysed cross-links with fibrillary hyperphosphorylated tau inclusions in tauopathies other than AD, using immunohistochemistry. We found strong TG1 and TG-catalysed cross-link staining in neuronal tau inclusions characteristic of PSP, FTDP-17 with mutations in the tau gene (FTDP-17T), and PiD brain, whereas, in contrast to AD, TG2 was only rarely observed in these inclusions. Furthermore, using a biochemical approach, we demonstrated that tau is a substrate for TG1-mediated cross-linking. Interestingly, we found co-localization of the TG1 activator, tazarotene-induced gene 3 (TIG3), in the neuronal tau inclusions of PSP, FTDP-17T, and PiD, but not in NFTs of AD cases, indicating that these tau-containing protein aggregates are not identical. We conclude that TG1-catalysed cross-linking, regulated by TIG3, might play an important role in the formation of neuronaltau inclusions in PSP, FTDP-17T, and PiD brain. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Phosphorylation of microtubule-associated protein tau by AMPK-related kinases.
Source
MRC Laboratory of Molecular Biology, Hills Road, Cambridge, UK.
Abstract
J. Neurochem. (2012) 120, 165-176. ABSTRACT: Microtubule-associated protein tau is abnormally hyperphosphorylatedin the intracellular filamentous inclusions seen in neurodegenerative disorders with dementia, such as Alzheimer's disease and other tauopathies. Microtubule-associated protein/microtubule-affinity regulating kinases (MARKs) have previously been identified as kinases which phosphorylate KxGS motifs in the tandem repeats of tau. They are members of the 5'-AMP-activated protein kinase (AMPK)-related kinases in the Ca(2+) /calmodulin-dependent protein kinase group. In this study, we examined the ability of AMPK-related kinases, brain-specific kinases 1 and 2, maternal embryonic leucine-zipper kinase, MARK1, and salt-inducible kinase (SIK), to phosphorylate tau. We found that they phosphorylated S262 and S356 in KxGS motifs in the repeats of tau, thus resulting in immunoreactivity with antibody 12E8. MARK1 and SIK most effectively phosphorylated tau, and their down-regulation resulted in a reduction of 12E8-labelling. BX 795, an inhibitor of MARK1 and SIK, reduced 12E8-immunolabelling of tau in rat cortical neurons. These findings reveal a significant contribution of AMPK-related kinases to the phosphorylation of tau at S262/S356.
© 2011 Medical Research Council. Journal of Neurochemistry © 2011 International Society for Neurochemistry.
Chronic stress exacerbates tau pathology, neurodegeneration, and cognitive performance through a corticotropin-releasing factor receptor-dependent mechanism in a transgenic mouse model of tauopathy.
Source
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, School of Medicine and Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Abstract
Because overactivation of the hypothalamic-pituitary-adrenal (HPA) axis occurs in Alzheimer's disease (AD), dysregulation of stress neuromediators may play a mechanistic role in the pathophysiology of AD. However, the effects of stress on tau phosphorylation are poorly understood, and the relationship between corticosterone and corticotropin-releasing factor (CRF) on both β-amyloid (Aβ) and tau pathology remain unclear. Therefore, we first established a model of chronic stress, which exacerbates Aβ accumulation in Tg2576 mice and then extended this stress paradigm to a tautransgenic mouse model with the P301S mutation (PS19) that displays tau hyperphosphorylation, insoluble tauinclusions and neurodegeneration. We show for the first time that both Tg2576 and PS19 mice demonstrate a heightened HPA stress profile in the unstressed state. In Tg2576 mice, 1 month of restraint/isolation (RI) stress increased Aβ levels, suppressed microglial activation, and worsened spatial and fear memory compared with nonstressed mice. In PS19 mice, RI stress promoted tau hyperphosphorylation, insoluble tau aggregation, neurodegeneration, and fear-memory impairments. These effects were not mimicked by chronic corticosterone administration but were prevented by pre-stress administration of a CRF receptor type 1 (CRF(1)) antagonist. The role for a CRF(1)-dependent mechanism was further supported by the finding that mice overexpressing CRF had increasedhyperphosphorylated tau compared with wild-type littermates. Together, these results implicate HPA dysregulation in AD neuropathogenesis and suggest that prolonged stress may increase Aβ and tau hyperphosphorylation. These studies also implicate CRF in AD pathophysiology and suggest that pharmacological manipulation of this neuropeptide may be a potential therapeutic strategy for AD.
Comment in
- PMID:
- 21976528
- [PubMed - indexed for MEDLINE]
- PMCID: PMC3230070
- [Available on 2012/4/5]
Improvement of the Detection of Neurodegenerative Alzheimer's Disease through a Specific Surface Chemistry Applied onto the Inner Surface of the Titration Well.
Abstract
The main objective of this paper was to illustrate the enhancement of the sensitivity of the ELISA titration of Tau proteinswhile reducing other non-specific adsorptions that could increase the optical densities and could lead to false positives. This goal was obtained thanks to the association of cold plasma and wet chemistries of the inner surface of the titration well. The PP surface was cold plasma-activated, then coated with different amphiphilic molecules bearing either ionic charges and/or long hydrocarbon chains. The support treated and coated with hexatrimethylammonium bromide improves the signal detection of proteins while reducing the background due to non-specific associations of biomolecules such as hyperphosphorylated Tau protein. However, coating with 3-butenylamine hydrochloride could also be suitable.
NMNAT suppresses Tau-induced neurodegeneration by promoting clearance ofhyperphosphorylated Tau oligomers in a Drosophila model of tauopathy.
Abstract
Tauopathies, including Alzheimer's disease, are a group of neurodegenerative diseases characterized by abnormal tauhyperphosphorylation that leads to formation of neurofibrillary tangles. Drosophila models of tauopathy display prominent features of the human disease including compromised lifespan, impairments of learning, memory and locomotor functions and age-dependent neurodegeneration visible as vacuolization. Here, we use a Drosophila model of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), in order to study the neuroprotective capacity of a recently identified neuronal maintenance factor, nicotinamide mononucleotide (NAD) adenylyl transferase (NMNAT), a protein that has both NAD synthase and chaperone function. NMNAT is essential for maintaining neuronal integrity under normal conditions and has been shown to protect against several neurodegenerative conditions. However, its protective role in tauopathy has not been examined. Here, we show that overexpression of NMNAT significantly suppresses both behavioral and morphological deficits associated with tauopathy by means of reducing the levels ofhyperphosphorylated tau oligomers. Importantly, the protective activity of NMNAT protein is independent of its NAD synthesis activity, indicating a role for direct protein-protein interaction. Next, we show that NMNAT interacts with phosphorylated tau in vivo and promotes the ubiquitination and clearance of toxic tau species. Consequently, apoptosis activation was significantly reduced in brains overexpressing NMNAT, and neurodegeneration was suppressed. Our report on the molecular basis of NMNAT-mediated neuroprotection in tauopathies opens future investigation of this factor in other protein foldopathies.
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