1.
Desmoplakin as a Potential Candidate for Cerebrospinal Fluid Marker to Rule Out 14-3-3 False Positive Rates in Sporadic Creutzfeldt-Jakob Disease Differential Diagnosis.
Source
National Reference Center for TSE Surveillance, Department of Neurology, Medical Center Georg August University, Göttingen, Germany.
Abstract
Background: The detection of a 14-3-3 elevated level in cerebrospinal fluid (CSF) is a part of the diagnostic criteria for probable sporadic Creutzfeldt-Jakob disease (sCJD), as defined by the WHO. However, some pathological conditions associated with acute neuronal damage may result in a positive 14-3-3 test and thereby reduce test specificity in sCJD. Objective: Desmoplakin has been previously identified as up-regulated CSF protein in sCJD and these studies aimed to investigate its diagnostic utility and compare it with two known CSF markers, 14-3-3 and tau. Methods and Results: We tested CSF levels of 14-3-3, tau and desmoplakin in 58 sCJD patients and 81 control patients including 45 cases with an elevated 14-3-3 level due to other disease than sCJD. We detected an elevated CSF level of desmoplakin in 78% of the sCJD patients, while 14-3-3 (88%) and tau (91%) showed a higher positive rate. However, the false positive rate of newly tested desmoplakin was significantly lower in comparison to 14-3-3 and tau, and it accounted for only 11% versus 56% and 35%, respectively. Further reduction of false positive rates was achieved by combination of elevated tau level with a positive desmoplakin test. Moreover, in the non-sCJD group, desmoplakin level did not correlate with the level of both above-mentioned CSF markers, whereas a clear correlation was observed in the sCJD group. Conclusion: Desmoplakin showed a low positive rate accompanied by a very low false positive rate. Thus, we conclude that desmoplakin is a promising candidate for supportive CSF marker to rule out 14-3-3 false positive cases in sCJD differential diagnosis.
Copyright © 2011 S. Karger AG, Basel.
- PMID:
- 22213780
- [PubMed - as supplied by publisher]
Isolation of synaptic terminals from Alzheimer's disease cortex.
Source
UCLA School of Nursing, Los Angeles, California 90095; UCLA Center for the Advancement of Gerontological Nursing Sciences, Los Angeles, California 90095; UCLA Brain Research Institute, Los Angeles, California 90095. ssokolow@sonnet.ucla.edu.
Abstract
Amyloid beta (Aβ) oligomers and phosphorylated tau (p-tau) aggregates are increasingly identified as potential toxic intermediates in Alzheimer's disease (AD). In cortical AD synapses, p-tau co-localizes with Aβ, but the Aβ and p-taupeptide species responsible for synaptic dysfunction and demise remains unclear. The present experiments were designed to use high-speed cell sorting techniques to purify synaptosome population based on size, and then extend the method to physically isolate Aβ-positive synaptosomes with the goal of understanding the nature of Aβ and taupathology in AD synapses. To examine the purity of size-gated synaptosomes, samples were first gated on size; particles with sizes between 0.5 and 1.5 microns were collected. Electron microscopy documented a homogenous population of spherical particles with internal vesicles and synaptic densities. Next, size-gated synaptosomes positive for Aβ were collected by fluorescence activated sorting and then analyzed by immunoblotting techniques. Sorted Aβ-positive synaptosomes were enriched for amyloid precursor protein (APP) and for Aβ oligomers and aggregates; immunolabeling for p-tau showed a striking accumulation of p-tau aggregates compared to the original homogenate and purified synaptosomes. These results confirm co-localization of Aβ and p-tau within individual synaptic terminals and provide proof of concept for the utility of flow sorting synaptosomes. © 2011 International Society for Advancement of Cytometry.
Copyright © 2011 International Society for Advancement of Cytometry.
- PMID:
- 22213704
- [PubMed - as supplied by publisher]
Transglutaminase 2: Biology, Relevance to Neurodegenerative Diseases and Therapeutic Implications.
Abstract
Neurodegenerative disorders are characterized by progressive neuronal loss and the aggregation of disease-specific pathogenic proteins in hallmark neuropathologic lesions. Many of these proteins, including amyloid Αβ, tau, α-synuclein and huntingtin, are cross-linked by the enzymatic activity of transglutaminase 2 (TG2). Additionally, the expression and activity of TG2 is increased in affected brain regions in these disorders. These observations along with experimental evidence in cellular and mouse models suggest that TG2 can contribute to the abnormal aggregation of disease causingproteins and consequently to neuronal damage. This accumulating evidence has provided the impetus to develop inhibitors of TG2 as possible neuroprotective agents. However, TG2 has other enzymatic activities in addition to its cross-linking function and can modulate multiple cellular processes including apoptosis, autophagy, energy production, synaptic function, signal transduction and transcription regulation. These diverse properties must be taken into consideration in designing TG2 inhibitors. In this review, we discuss the biochemistry of TG2, its various physiologic functions and our current understanding about its role in degenerative diseases of the brain. We also describe the different approaches to designing TG2 inhibitors that could be developed as potential disease-modifying therapies.
Copyright © 2011. Published by Elsevier Inc.
- PMID:
- 22212614
- [PubMed - as supplied by publisher]
Management of moderate to severe Alzheimer's disease: Focus on memantine.
Source
Department of Bioscience Technology, Chung Yuan Christian University, Chung Li, Taiwan.
Abstract
Alzheimer's disease (AD) is the most common form of dementia, and one of the principal causes leading to death around the world. It is a progressive neurodegenerative disorder that still remains without definite cure. Memantine, a licensed AD drug, is an open-channel and partial trapping blocker that functions as a potent NMDA receptor antagonist, even at low concentrations. Aside from being uncompetitive, it also allows near-normal physiological NMDA receptor activity throughout the brain even with high glutamate concentrations, making it more reliable and tolerable than other AD-targeted drugs. It has also been found to be effective, safe, and well-tolerated in animal models as well as patients with moderate-to-severe AD. Aside from NMDA receptor antagonism, numerous studies have reported that memantine can also affect dopamine receptors, block excessive calcium influx and production of reactive oxygen species (ROS) induced by Aβ oligomers, and inhibit the internal ribosome entry site (IRES), thus preventing the expression of the amyloid precursor and tau proteins which are considered as early indicators of Alzheimer's.
Copyright © 2011. Published by Elsevier B.V.
- PMID:
- 22212311
- [PubMed - in process]
Altered CSF Orexin and α-Synuclein Levels in Dementia Patients.
Source
Molecular Memory Research Unit, The Wallenberg Lab, Lund University, Department of Clinical Sciences Malmö, Sweden.
Abstract
Neurodegenerative dementia, most frequently represented by Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), is often accompanied by altered sleeping patterns and excessive daytime sleepiness. Studies showing an association between the neuropeptide orexin and AD/DLB-related processes such as amyloid-β (Aβ)1-42 plaque formation, α-synuclein accumulation, and inflammation indicate that orexin might play a pathogenic role similar to the situation in narcolepsy. Our study of patients with AD (n = 26), DLB (n = 18), and non-demented controls (n = 24) shows a decrease in cerebrospinal fluid (CSF) orexin concentrations in DLB versus AD patients and controls. The observed differences in orexin levels were found to be specific to female DLB patients. We also show that the female DLB patients exclusively displayed lower levels of α-synuclein compared to AD patients and controls. Orexin was linked to α-synuclein and total-tau in female non-demented controls whereas associations between orexin and Aβ1-42 concentrations were absent in all groups regardless of gender. Thus, the proposed links between orexin, Aβ, and α-synuclein pathology could not be monitored in CSF protein concentrations. Interestingly, α-synuclein was strongly correlated to the CSF levels of total-tau in all groups, suggesting α-synuclein to be an unspecific marker of neurodegeneration. We conclude that lower levels of CSF orexin are specific to DLB versus AD and appear unrelated to Aβ1-42 and α-synuclein levels in AD and DLB. Alterations in CSF orexin and α-synuclein levels may be related to gender which warrants further investigation.
Calpastatin modulates APP processing in the brains of β-amyloid depositing but not wild-type mice.
Source
Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA; New York University School of Medicine, New York, NY, USA.
Abstract
We report that neuronal overexpression of the endogenous inhibitor of calpains, calpastatin (CAST), in a mouse model of human Alzheimer's disease (AD) β-amyloidosis, the APP23 mouse, reduces β-amyloid (Aβ) pathology and Aβ levels when comparing aged, double transgenic (tg) APP23/CAST with APP23 mice. Concurrent with Aβ plaque deposition, aged APP23/CAST mice show a decrease in the steady-state brain levels of the amyloid precursor protein (APP) and APP C-terminal fragments (CTFs) when compared with APP23 mice. This CAST-dependent decrease in APP metabolite levels was not observed in single tg CAST mice expressing endogenous APP or in younger, Aβ plaque predepositing APP23/CAST mice. We also determined that the CAST-mediated inhibition of calpain activity in the brain is greater in the CAST mice with Aβ pathology than in non-APP tg mice, as demonstrated by a decrease in calpain-mediated cytoskeleton protein cleavage. Moreover, aged APP23/CAST mice have reduced extracellular signal-regulated kinase 1/2 (ERK1/2) activity and tau phosphorylation when compared with APP23 mice. In summary, in vivo calpain inhibition mediated by CAST transgene expression reduces Aβ pathology in APP23 mice, with our findings further suggesting that APP metabolism is modified by CAST overexpression as the mice develop Aβ pathology. Our results indicate that the calpain system in neurons is more responsive to CAST inhibition under conditions of Aβ pathology, suggesting that in the disease state neurons may be more sensitive to the therapeutic use of calpain inhibitors.
Copyright © 2011 Elsevier Inc. All rights reserved.
Phosphorus Dendrimers Affect Alzheimer's (Aβ1-28) Peptide and MAP-Tau Protein Aggregation.
Abstract
Alzheimer's disease (AD) is characterized by pathological aggregation of β-amyloid peptides and MAP-Tau protein. β-amyloid (Aβ) is a peptide responsible for extracellular Alzheimer's plaque formation. Intracellular MAP-Tau aggregates appear as a result of hyperphosphorylation of this cytoskeletal protein. Small, oligomeric forms of Aβ are intermediate products that appear before the amyloid plaques are formed. These forms are believed to be most neurotoxic. Dendrimers are highly branched polymers, which may find an application in regulation of amyloid fibril formation. Several biophysical and biochemical methods, like circular dichroism (CD), fluorescence intensity of thioflavin T and thioflavin S, transmission electron microscopy, spectrofluorimetry (measuring quenching of intrinsic peptide fluorescence) and MTT-cytotoxicity assay, were applied to characterize interactions of cationic phosphorus-containing dendrimers of generation 3 and generation 4 (CPDG3, CPDG4) with the fragment of amyloid peptide (Aβ1-28) and MAP-Tau protein. We have demonstrated that CPDs are able to affect β-amyloid and MAP-Tau aggregation processes. A neuro-2a cell line (N2a) was used to test cytotoxicity of formed fibrils and intermediate products during the Aβ1-28 aggregation. It has been shown that CPDs might have a beneficial effect by reducing the system toxicity. Presented results suggest that phosphorus dendrimers may be used in the future as agents regulating the fibrilization processes in Alzheimer's disease.
Tau reduction does not prevent motor deficits in two mouse models of Parkinson's disease.
Source
Gladstone Institute of Neurological Disease, San Francisco, California, United States of America.
Abstract
Many neurodegenerative diseases are increasing in prevalence and cannot be prevented or cured. If they shared common pathogenic mechanisms, treatments targeting such mechanisms might be of benefit in multiple conditions. The tau protein has been implicated in the pathogenesis of diverse neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Tau reduction prevents cognitive deficits, behavioral abnormalities and other pathological changes in multiple AD mouse models. Here we examined whether tau reduction also prevents motor deficits and pathological alterations in two mouse models of PD, generated by unilateral striatal injection of 6-hydroxydopamine (6-OHDA) or transgene-mediated neuronal expression of human wildtype α-synuclein. Both models were evaluated on Tau(+/+), Tau(+/-) and Tau(-/-) backgrounds in a variety of motor tests. Tau reduction did not prevent motor deficits caused by 6-OHDA and slightly worsened one of them. Tau reduction also did not prevent 6-OHDA-induced loss of dopaminergic terminals in the striatum. Similarly, tau reduction did not prevent motor deficits in α-synuclein transgenic mice. Our results suggest that tau has distinct roles in the pathogeneses of AD and PD and thattau reduction may not be of benefit in the latter condition.
Regulation of Physiologic Actions of LRRK2: Focus on Autophagy.
Source
Department of Pharmacology, Boston University School of Medicine, Boston, Mass., USA.
Abstract
Background: Mutations in LRRK2 are associated with familial and sporadic Parkinson's disease (PD). Subjects with PD caused by LRRK2 mutations show pleiotropic pathology that can involve inclusions containing α-synuclein, tau or neither protein. The mechanisms by which mutations in LRRK2 lead to this pleiotropic pathology remain unknown. Objectives: To investigate mechanisms by which LRRK2 might cause PD. Methods: We used systems biology to investigate the transcriptomes from human brains, human blood cells and Caenorhabditis elegans expressing wild-type LRRK2. The role of autophagy was tested in lines of C. elegans expressing LRRK2, V337M tau or both proteins. Neuronal function was measured by quantifying thrashing. Results: Genes regulating autophagy were coordinately regulated with LRRK2. C. elegans expressing V337M tau showed reduced thrashing, as has been noted previously. Coexpressing mutant LRRK2 (R1441C or G2019S) with V337M tau increased the motor deficits. Treating the lines of C. elegans with an mTOR inhibitor that enhances autophagic flux, ridaforolimus, increased the thrashing behavior to the same level as nontransgenic nematodes. Conclusion: These data support a role for LRRK2 in autophagy, raise the possibility that deficits in autophagy contribute to the pathophysiology of LRRK2, and point to a potential therapeutic approach addressing the pathophysiology of LRRK2 in PD.
Copyright © 2011 S. Karger AG, Basel.
Therapeutic targets of brain insulin resistance in sporadic Alzheimer's disease.
Source
Departments of Neurology, Neurosurgery, and Neuropathology, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI.
Abstract
Growing evidence supports roles for brain insulin and insulin-like growth factor (IGF) resistance and metabolic dysfunction in the pathogenesis of Alzheimer's disease (AD). Whether the underlying problem stems from a primary disorder of central nervous system (CNS) neurons and glia, or secondary effects of systemic diseases such as obesity, Type 2 diabetes, or metabolic syndrome, the end-results include impaired glucose utilization, mitochondrial dysfunction, increased oxidative stress, neuroinflammation, and the propagation of cascades that result in the accumulation of neurotoxic misfolded, aggregated, and ubiquitinated fibrillar proteins. This article reviews the roles of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism, and discusses therapeutic strategies and lifestyle approaches that could be used to prevent, delay the onset, or reduce the severity of AD. Finally, it is critical to recognize that AD is heterogeneous and has a clinical course that fully develops over a period of several decades. Therefore, early and multi-modal preventive and treatment approaches should be regarded as essential.
- PMID:
- 22201977
- [PubMed - in process]
The tau-like protein in silkworm (Bombyx mori) induces microtubule bundle formation.
Source
The Key Laboratory of Cell Proliferation and Differentiation of Ministry of Education; The State Key Laboratory of Bio-membrane and Membrane Bio-engineering, College of Life Sciences, Peking University, Beijing 100871, China.
Abstract
Tau proteins are major microtubule-associated proteins (MAPs), which promote polymerization of tubulin and determine spacings between microtubules in axons of both the central and peripheral nervous systems (CNS and PNS). Here, we cloned and identified a tau-like protein BmTau from silkworm, Bombyx mori (GenBank accession number FJ904935). The coding sequence of BmTau is 723 bases long and encodes an approximate 30kDa protein. In the C-terminus of BmTau are contained four predicted microtubule-binding domains, which share strong sequence homology to its ortholog in Drosophila melanoganster. Relative real-time PCR analysis showed ubiquitous expression of BmTau in both neurons and non-neural cells, with its mRNA abundantly expressing in brain but significantly less detected in trachea, fat body, and silkgland. Furthermore, immunocytochemical studies in BmN cells transfected with EGFP-BmTau indicated that BmTau functioned as microtubule bundling protein as its orthologues.
- PMID:
- 22201930
- [PubMed - in process]
Metals in alzheimer's disease: a systemic perspective.
Source
Department of Neuroscience, AFaR, Fatebenefratelli Hospital, Rome, Italy, Department of Neurology, Campus Biomedico, University, Rome, Italy.
Abstract
Many results from in vitro and animal studies have highlighted the important role played by specific metals, such as copper, iron and zinc, in the diverse toxic pathways on which Alzheimer's disease (AD) develops. Metals seem to mediate the aggregation and neurotoxicity of amyloid-beta (ABeta), the main constituent of the amyloid plaques, commonly seen in AD (1). The link between metals and AD has been mostly investigated with a focus on their local accumulation in defined areas of the brain critical for AD. In the present review, I have instead approached the issue from the different perspective of a systemic, rather than local, alteration of copper and iron status. This view is supported by the results of a series of in vivo studies demonstrating that abnormalities of metals homeostasis correlate with the main deficits and specific markers of AD, such as ABeta and Tau proteins in the cerebrospinal fluid. These findings clearly suggest that local metals accumulation in brain areas critical for AD should be viewed within a wider framework of metals systemic alteration.
- PMID:
- 22201755
- [PubMed - in process]
Does Alzheimer's disease exist in all primates? Alzheimer pathology in non-human primates and its pathophysiological implications (I).
Source
Instituto Cajal, CSIC, Madrid, España.
Abstract
INTRODUCTION:
Many publications consider that the Alzheimer's disease (AD) is exclusive to the human species, and that no other animal species suffers from the disease. However, various studies have shown that some species can present with some of the defining characteristics of the disease in humans, both in the neuropathological changes and cognitive-behavioural symptoms.
DEVELOPMENT:
In this work, the results published (PubMed) on the senile brain changes in non-human primates of different degrees of evolution, are reviewed. The neuropathological changes associated with the accumulation of amyloid or highly phosphorylated tau protein are rare outside the primate order, but in all the sub-orders, families, genera and species of non-human primates that have been studied, some senile individuals have shown amyloid accumulation in the brain. Even in some species the presence of these deposits in senility is constant. Changes related to the accumulation of tau protein, are always of very little significance, and have been detected only in some non-human primate species, both little evolved and highly evolved. In different species of non-human primates, some types of cognitive-behavioural changes are present in some senile individuals with greater intensity when compared with both normal adult individuals and other senile individuals of the species. The importance of the determination of the longevity of the species in different habitats (natural habitats, new habitats, semi-liberty, captivity) is stressed in these studies.
CONCLUSIONS:
Morphological and histochemical and cognitive-behavioural features similar to those observed in normal aged man are present in senile non-human primates. Moreover, other characteristics of the non-human primates could be indicative of a pathological «Alzheimer type» ageing.
Copyright © 2011 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.
Isoflurane-induced spatial memory impairment by a mechanism independent of amyloid-beta levels and tau protein phosphorylation changes in aged rats.
Source
Chaoyang Hospital, Capital Medical University, Beijing, China.
Abstract
OBJECTIVES:
The molecular mechanism of postoperative cognitive dysfunction is largely unknown. Isoflurane has been shown to promote Alzheimer's disease neuropathogenesis. We set out to determine whether the effect of isoflurane on spatial memory is associated with amyloid-beta (A-beta) levels and tau phosphorylation in aged rats.
METHODS:
Eighteen-month-old male Sprague-Dawley rats were randomly assigned as anesthesia group (n = 31, received 1·4% isoflurane for 2 hours and had behavioral testing), training group (n = 20, received no anesthesia but had behavioral testing), and control group (n = 10, received no anesthesia and had no behavioral testing). Spatial memory was measured before and 2 days after the anesthesia by the Morris water maze. We divided the anesthesia group into an isoflurane-induced severe memory impairment group (SIG, n = 6) and a no severe memory impairment group (NSIG, n = 25), according to whether the escape latency was more than 1·96 stand deviation of that from the training group. Levels of A-beta and tau in the hippocampus were determined by enzyme-linked immunosorbent assay and quantitative western blot at the end of behavioral testing.
RESULTS:
We found that isoflurane increased the escape latency in the SIG as compared to that in the training group and NSIG without affecting swimming speed. However, there were no differences in the levels of A-beta and tau among SIG, NSIG, training, and control groups.
CONCLUSIONS:
Isoflurane may induce spatial memory impairment through non-A-beta or tau neuropathogenesis mechanisms in aged rats.
- PMID:
- 22196855
- [PubMed - in process]
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.
Lidocaine attenuates cognitive impairment after isoflurane anesthesia in old rats.
Source
Department of Anesthesiology, University of Virginia, Charlottesville, VA 22908, USA; Department of Anesthesiology, Sun-Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou 510120, Guangdong, China.
Abstract
Post-operative cognitive dysfunction (POCD) is a clinical phenomenon that has drawn significant attention from the public and scientific community. Age is a risk factor for POCD. However, the contribution of general anesthesia/anesthetics to POCD and the underlying neuropathology are not clear. Here, we showed that 18-month-old male Fisher 344 rats exposed to 1.2% isoflurane, a general anesthetic, for 2h had significant learning and memory impairments assessed at 2-4 weeks after isoflurane exposure. These isoflurane effects were attenuated by intravenous lidocaine (1.5mg/kg as a bolus and then 2mg/kg/h during isoflurane exposure), a local anesthetic that has neuroprotective effect. Exposure to isoflurane or isoflurane plus lidocaine did not change the neuronal and synaptic density as well as the expression of NeuN (a neuronal protein), drebrin (a dendritic spine protein), synaptophysin (a synaptic protein), activated caspase 3 and caspase-activated DNase in the hippocampus at 29 days after isoflurane exposure when cognitive impairment was present. Isoflurane and lidocaine did not affect the amount of β-amyloid peptide, total tau and phospho-tau in the cerebral cortex as well as interleukin-1β and tumor necrosis factor-α in the hippocampus at 29 days after isoflurane exposure. Thus, isoflurane induces learning and memory impairment in old rats. Lidocaine attenuates these isoflurane effects. Isoflurane may not cause long-lasting neuropathological changes.
Copyright © 2011. Published by Elsevier B.V.
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.
Efficient algorithms for reconstructing gene content by co-evolution.
Source
Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel. tamirtul@post.tau.ac.il.
Abstract
BACKGROUND:
In a previous study we demonstrated that co-evolutionary information can be utilized for improving the accuracy of ancestral gene content reconstruction. To this end, we defined a new computational problem, the Ancestral Co-Evolutionary (ACE) problem, and developed algorithms for solving it.
RESULTS:
In the current paper we generalize our previous study in various ways. First, we describe new efficient computational approaches for solving the ACE problem. The new approaches are based on reductions to classical methods such as linear programming relaxation, quadratic programming, and min-cut. Second, we report new computational hardness results related to the ACE, including practical cases where it can be solved in polynomial time.Third, we generalize the ACE problem and demonstrate how our approach can be used for inferring parts of the genomes of non-ancestral organisms. To this end, we describe a heuristic for finding the portion of the genome ('dominant set') that can be used to reconstruct the rest of the genome with the lowest error rate. This heuristic utilizes both evolutionary information and co-evolutionary information.We implemented these algorithms on a large input of the ACE problem (95 unicellular organisms, 4,873 protein families, and 10, 576 of co-evolutionary relations), demonstrating that some of these algorithms can outperform the algorithm used in our previous study. In addition, we show that based on our approach a 'dominant set' cab be used reconstruct a major fraction of a genome (up to 79%) with relatively low error-rate (e.g. 0.11). We find that the 'dominant set' tends to include metabolic and regulatory genes, with high evolutionary rate, and low protein abundance and number of protein-protein interactions.
CONCLUSIONS:
The ACE problem can be efficiently extended for inferring the genomes of organisms that exist today. In addition, it may be solved in polynomial time in many practical cases. Metabolic and regulatory genes were found to be the most important groups of genes necessary for reconstructing gene content of an organism based on other related genomes.
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.
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