Publications by authors named "Tariq Ahmed"

50 Publications

Fourier Transform Infrared Imaging-A Novel Approach to Monitor Bio Molecular Changes in Subacute Mild Traumatic Brain Injury.

Brain Sci 2021 Jul 12;11(7). Epub 2021 Jul 12.

Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar.

Traumatic brain injury (TBI) can be defined as a disorder in the function of the brain after a bump, blow, or jolt to the head, or penetrating head injury. Mild traumatic brain injury (mTBI) can cause devastating effects, such as the initiation of long-term neurodegeneration in brain tissue. In the current study, the effects of mTBI were investigated on rat brain regions; cortex (Co) and corpus callosum (CC) after 24 h (subacute trauma) by Fourier transform infrared (FTIR) imaging and immunohistochemistry (IHC). IHC studies showed the formation of amyloid-β (Aβ) plaques in the cortex brain region of mTBI rats. Moreover, staining of myelin basic protein presented the shearing of axons in CC region in the same group of animals. According to FTIR imaging results, total protein and lipid content significantly decreased in both Co and CC regions in mTBI group compared to the control. Due to this significant decrease in both lipid and protein content, remarkable consistency in lipid/protein band ratio in mTBI and control group, was observed. Significant decrease in methyl content and a significant increase in olefinic content were observed in Co and CC regions of mTBI rat brain tissues. Classification amongst distinguishable groups was performed using principal component analysis (PCA) and hierarchical clustering (HCA). This study established the prospective of FTIR imaging for assessing biochemical changes due to mTBI with high sensitivity, precision and high-resolution.
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http://dx.doi.org/10.3390/brainsci11070918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307811PMC
July 2021

Prognostic value of GRACE score for in-hospital and 6 months outcomes after non-ST elevation acute coronary syndrome.

Egypt Heart J 2021 Mar 6;73(1):22. Epub 2021 Mar 6.

Government of Sindh, Karachi, Pakistan.

Background: The aim of this study was to determine the predictive value of the Global Registry of Acute Coronary Events (GRACE) score for predicting in-hospital and 6 months mortality after non-ST elevation acute coronary syndrome (NSTE-ACS).

Results: In this observational study, 300 patients with NSTE-ACS of age more than 30 years were included; 16 patients died during the hospital stay (5.3%). Of 284 patients at 6 months assessment, 10 patients died (3.5%), 240 survived (84.5%), and 34 were lost to follow-up (12%) respectively. In high risk category, 10.5% of the patients died within hospital stay and 11.8% died within 6 months (p = 0.001 and p = 0.013). In univariate analysis, gender, diabetes mellitus, family history, smoking, and GRACE score were significantly associated with in-hospital mortality whereas age, obesity, dyslipidemia, and GRACE were significantly associated with 6 months mortality. After adjustment, diabetes mellitus, family history, and GRACE score remained significantly associated with in-hospital mortality (p ≤ 0.05) and age remained significantly associated with 6 months mortality.

Conclusion: GRACE risk score has good predictive value for the prediction of in-hospital mortality and 6 months mortality among patients with NSTE-ACS.
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http://dx.doi.org/10.1186/s43044-021-00146-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937004PMC
March 2021

Biomolecular alterations in acute traumatic brain injury (TBI) using Fourier transform infrared (FTIR) imaging spectroscopy.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Mar 13;248:119189. Epub 2020 Nov 13.

Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar. Electronic address:

Acute injury is one of the substantial stage post-traumatic brain injury (TBI) occurring at the moment of impact. Decreased metabolism, unregulated cerebral blood flow and direct tissue damage are triggered by acute injury. Understating the biochemical alterations associated with acute TBI is critical for brain plasticity and recovery. The objective of this study was to investigate the biochemical and molecular changes in hippocampus, corpus callosum and thalamus brain regions post-acute TBI in rats. Fourier Transform Infrared (FTIR) imaging spectroscopy were used to collect chemical images from control and 3 hrs post-TBI (Marmarou model was used for the TBI induction) rat brains and adjacent sections were treated by hematoxylin and eosin (H&E) staining to correlate with the disruption in tissue morphology and injured brain biochemistry. Our results revealed that the total lipid and total protein content decreased significantly in the hippocampus, corpus callosum and thalamus after brain injury. Reduction in lipid acyl chains (-CH) associated with an increase in methyl (-CH) and unsaturated lipids olefin = CH concentrations is observed. Furthermore, there is a decrease in the lipid order (disorder), which leads to an increase in acyl chain fluidity in injured rats. The results suggest acute TBI damages brain tissues mechanically rather than chemical alterations. This will help in assessing successful therapeutic strategy in order to mitigate tissue damage in acute TBI period.
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http://dx.doi.org/10.1016/j.saa.2020.119189DOI Listing
March 2021

Imaging Markers for the Characterization of Gray and White Matter Changes from Acute to Chronic Stages after Experimental Traumatic Brain Injury.

J Neurotrauma 2021 Jun 11;38(12):1642-1653. Epub 2021 Jan 11.

Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands. ORCID ID: 0000-0002-8185-9209; 0000-0002-4623-4078.

Despite clinical symptoms, a large majority of people with mild traumatic brain injury (TBI) have normal computed tomography (CT) and magnetic resonance imaging (MRI) scans. Therefore, present-day neuroimaging tools are insufficient to diagnose or classify low grades of TBI. Advanced neuroimaging techniques, such as diffusion-weighted and functional MRI, may yield novel biomarkers that may aid in the diagnosis of TBI. Therefore, the present study had two aims: first, to characterize the development of MRI-based measures of structural and functional changes in gray and white matter regions from acute to chronic stages after mild and moderate TBI; and second, to identify the imaging markers that can most accurately predict outcome after TBI. To these aims, 52 rats underwent serial functional (resting-state) and structural (T1-, T2-, and diffusion-weighted) MRI before and 1 h, 1 day, 1 week, 1 month and 3-4 months after mild or moderate experimental TBI. All rats underwent behavioral testing. Histology was performed in subgroups of rats at different time points. Early after moderate TBI, axial and radial diffusivities were increased, and fractional anisotropy was reduced in the corpus callosum and bilateral hippocampi, which normalized over time and was paralleled by recovery of sensorimotor function. Correspondingly, histology revealed decreased myelin staining early after TBI, which was not detected at chronic stages. No significant changes in individual outcome measures were detected after mild TBI. However, multivariate analysis showed a significant additive contribution of diffusion parameters in the distinction between control and different grades of TBI-affected brains. Therefore, combining multiple imaging markers may increase the sensitivity for TBI-related pathology.
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http://dx.doi.org/10.1089/neu.2020.7151DOI Listing
June 2021

Chronic Sodium Selenate Treatment Restores Deficits in Cognition and Synaptic Plasticity in a Murine Model of Tauopathy.

Front Mol Neurosci 2020 8;13:570223. Epub 2020 Oct 8.

Brain and Cognition, Faculty of Psychology and Educational Sciences, KU Leuven, Leuven, Belgium.

A major goal in diseases is identifying a potential therapeutic agent that is cost-effective and can remedy some, if not all, disease symptoms. In Alzheimer's disease (AD), aggregation of hyperphosphorylated tau protein is one of the neuropathological hallmarks, and Tau pathology correlates better with cognitive impairments in AD patients than amyloid-β load, supporting a key role of tau-related mechanisms. Selenium is a non-metallic trace element that is incorporated in the brain into selenoproteins. Chronic treatment with sodium selenate, a non-toxic selenium compound, was recently reported to rescue behavioral phenotypes in tau mouse models. Here, we focused on the effects of chronic selenate application on synaptic transmission and synaptic plasticity in THY-Tau22 mice, a transgenic animal model of tauopathies. Three months with a supplement of sodium selenate in the drinking water (12 μg/ml) restored not only impaired neurocognitive functions but also rescued long-term depression (LTD), a major form of synaptic plasticity. Furthermore, selenate reduced the inactive demethylated catalytic subunit of protein phosphatase 2A (PP2A) in THY-Tau22 without affecting total PP2A.Our study provides evidence that chronic dietary selenate rescues functional synaptic deficits of tauopathy and identifies activation of PP2A as the putative mechanism.
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http://dx.doi.org/10.3389/fnmol.2020.570223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578417PMC
October 2020

Extraarticular extrasynovial solitary osteochondromatosis of the ankle: A rare case report and review of literature.

Int J Surg Case Rep 2020 31;75:61-65. Epub 2020 Aug 31.

Apollo Hospital, Muscat, Oman.

Introduction: Synovial chondromatosis (SC) is a relatively common benign condition of the synovial joint characterized by the formation of cartilaginous nodules in synovium. However, extra articular osteochondromatosis is rare and only few have been reported around the ankle joint. We have reported such a presentation and have reviewed the literature extensively.

Presentation Of Case: We present a 26 year old male patient with a painless swelling over the lateral aspect of his left ankle. He was subjected to clinical and radiological examination which revealed a firm to hard swelling around the lateral malleolus and a lobulated juxtacortical cystic lesion with calcification. He underwent a surgical excision and subsequent histopathology was suggestive of SC.

Discussion: The subtle clinical and radiological presentation of SC can lead to both a delay in the diagnosis and a diagnostic dilemma if suspicion is low. Early meticulous diagnosis and management can curtail morbidity.

Conclusion: The degree of suspicion needs to be high to diagnose the condition early to prevent both morbidity and inadequate treatment. Histopathological corroboration is needed to rule out uncommon but possible malignant transformation, notably in long standing cases.
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http://dx.doi.org/10.1016/j.ijscr.2020.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490981PMC
August 2020

The two faces of synaptic failure in App knock-in mice.

Alzheimers Res Ther 2020 08 24;12(1):100. Epub 2020 Aug 24.

Brain and Cognition, KU Leuven, Tiensestraat 102, Box 3714, 3000, Leuven, Belgium.

Background: Intensive basic and preclinical research into Alzheimer's disease (AD) has yielded important new findings, but they could not yet been translated into effective therapies. One of the reasons is the lack of animal models that sufficiently reproduce the complexity of human AD and the response of human brain circuits to novel treatment approaches. As a step in overcoming these limitations, new App knock-in models have been developed that avoid transgenic APP overexpression and its associated side effects. These mice are proposed to serve as valuable models to examine Aß-related pathology in "preclinical AD."

Methods: Since AD as the most common form of dementia progresses into synaptic failure as a major cause of cognitive deficits, the detailed characterization of synaptic dysfunction in these new models is essential. Here, we addressed this by extracellular and whole-cell patch-clamp recordings in App mice compared to App animals which served as controls.

Results: We found a beginning synaptic impairment (LTP deficit) at 3-4 months in the prefrontal cortex of App mice that is further aggravated and extended to the hippocampus at 6-8 months. Measurements of miniature EPSCs and IPSCs point to a marked increase in excitatory and inhibitory presynaptic activity, the latter accompanied by a moderate increase in postsynaptic inhibitory function.

Conclusions: Our data reveal a marked impairment of primarily postsynaptic processes at the level of synaptic plasticity but the dominance of a presumably compensatory presynaptic upregulation at the level of elementary miniature synaptic function.
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http://dx.doi.org/10.1186/s13195-020-00667-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445922PMC
August 2020

Design and capital cost optimisation of three-phase gravity separators.

Heliyon 2020 Jun 23;6(6):e04065. Epub 2020 Jun 23.

School of Computing, Engineering and Digital Technologies, Teesside University, UK.

The separation of produced fluids is essential once it reaches the surface. This separation is achieved in gravity separators. The design and sizing of separators can be challenging due to the number of factors involved. Improper separator design can bottleneck and reduce the production of the entire facility. This paper describes the development of a capital cost optimisation model for sizing three phase separators. The developed model uses GRG Non-linear algorithms to determine the minimum cost associated with the construction of horizontal separators subject to four sets of constraints. A numerical sizing example was solved to provide the details associated with the model and the ease with which parameters can be varied to suit the user's needs. Finally, a spreadsheet comparison between results obtained from the developed model and four other extant models is carried out. Results indicated that the developed model predicted results within an absolute error of ±5m in most cases and a maximum of ±12.5m for very high gas flows in comparison to conventional models developed based on retention time theory.
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http://dx.doi.org/10.1016/j.heliyon.2020.e04065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321976PMC
June 2020

Syndapin I Loss-of-Function in Mice Leads to Schizophrenia-Like Symptoms.

Cereb Cortex 2020 06;30(8):4306-4324

Institute of Biochemistry I, Jena University Hospital-Friedrich Schiller University Jena, 07743 Jena, Germany.

Schizophrenia is associated with cognitive and behavioral dysfunctions thought to reflect imbalances in neurotransmission systems. Recent screenings suggested that lack of (functional) syndapin I (PACSIN1) may be linked to schizophrenia. We therefore studied syndapin I KO mice to address the suggested causal relationship to schizophrenia and to analyze associated molecular, cellular, and neurophysiological defects. Syndapin I knockout (KO) mice developed schizophrenia-related behaviors, such as hyperactivity, reduced anxiety, reduced response to social novelty, and an exaggerated novel object response and exhibited defects in dendritic arborization in the cortex. Neuromorphogenic deficits were also observed for a schizophrenia-associated syndapin I mutant in cultured neurons and coincided with a lack of syndapin I-mediated membrane recruitment of cytoskeletal effectors. Syndapin I KO furthermore caused glutamatergic hypofunctions. Syndapin I regulated both AMPAR and NMDAR availabilities at synapses during basal synaptic activity and during synaptic plasticity-particularly striking were a complete lack of long-term potentiation and defects in long-term depression in syndapin I KO mice. These synaptic plasticity defects coincided with alterations of postsynaptic actin dynamics, synaptic GluA1 clustering, and GluA1 mobility. Both GluA1 and GluA2 were not appropriately internalized. Summarized, syndapin I KO led to schizophrenia-like behavior, and our analyses uncovered associated molecular and cellular mechanisms.
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http://dx.doi.org/10.1093/cercor/bhaa013DOI Listing
June 2020

Tau- but not Aß -pathology enhances NMDAR-dependent depotentiation in AD-mouse models.

Acta Neuropathol Commun 2019 12 9;7(1):202. Epub 2019 Dec 9.

Brain & Cognition, Faculty of Psychology and Educational Sciences, K.U.Leuven, Tiensestraat 102, 3000, Leuven, Belgium.

Many mouse models of Alzheimer's disease (AD) exhibit impairments in hippocampal long-term-potentiation (LTP), seemingly corroborating the strong correlation between synaptic loss and cognitive decline reported in human studies. In other AD mouse models LTP is unaffected, but other defects in synaptic plasticity may still be present. We recently reported that THY-Tau22 transgenic mice, that overexpress human Tau protein carrying P301S and G272 V mutations and show normal LTP upon high-frequency-stimulation (HFS), develop severe changes in NMDAR mediated long-term-depression (LTD), the physiological counterpart of LTP. In the present study, we focused on putative effects of AD-related pathologies on depotentiation (DP), another form of synaptic plasticity. Using a novel protocol to induce DP in the CA1-region, we found in 11-15 months old male THY-Tau22 and APPPS1-21 transgenic mice that DP was not deteriorated by Aß pathology while significantly compromised by Tau pathology. Our findings advocate DP as a complementary form of synaptic plasticity that may help in elucidating synaptic pathomechanisms associated with different types of dementia.
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http://dx.doi.org/10.1186/s40478-019-0813-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902514PMC
December 2019

Perispinal injection of a TNF blocker directed to the brain of rats alleviates the sensory and affective components of chronic constriction injury-induced neuropathic pain.

Brain Behav Immun 2019 11 31;82:93-105. Epub 2019 Jul 31.

Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, USA; Program for Neuroscience, University at Buffalo, The State University of New York, USA. Electronic address:

Neuropathic pain is chronic pain that follows nerve injury, mediated in the brain by elevated levels of the inflammatory protein tumor necrosis factor-alpha (TNF). We have shown that peripheral nerve injury increases TNF in the hippocampus/pain perception region, which regulates neuropathic pain symptoms. In this study we assessed pain sensation and perception subsequent to specific targeting of brain-TNF (via TNF antibody) administered through a novel subcutaneous perispinal route. Neuropathic pain was induced in Sprague-Dawley rats via chronic constriction injury (CCI), and thermal hyperalgesia was monitored for 10 days post-surgery. On day 8 following CCI and sensory pain behavior testing, rats were randomized to receive perispinal injection of TNF antibody or control IgG isotype antibody. Pain perception was assessed using conditioned place preference (CPP) to the analgesic, amitriptyline. CCI-rats receiving the perispinal injection of TNF antibody had significantly decreased CCI-induced thermal hyperalgesia the following day, and did not form an amitriptyline-induced CPP, whereas CCI-rats receiving perispinal IgG antibody experienced pain alleviation only in conjunction with i.p. amitriptyline and did form an amitriptyline-induced CPP. The specific targeting of brain TNF via perispinal delivery alleviates thermal hyperalgesia and positively influences the affective component of pain. PERSPECTIVE: This study presents a novel route of drug administration to target central TNF for treatment of neuropathic pain. Targeting central TNF through perispinal drug delivery could potentially be a more efficient and sustained method to treat patients with neuropathic pain.
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http://dx.doi.org/10.1016/j.bbi.2019.07.036DOI Listing
November 2019

Age-associated cholesterol reduction triggers brain insulin resistance by facilitating ligand-independent receptor activation and pathway desensitization.

Aging Cell 2019 06 18;18(3):e12932. Epub 2019 Mar 18.

Department of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Madrid, Spain.

In the brain, insulin plays an important role in cognitive processes. During aging, these faculties decline, as does insulin signaling. The mechanism behind this last phenomenon is unclear. In recent studies, we reported that the mild and gradual loss of cholesterol in the synaptic fraction of hippocampal neurons during aging leads to a decrease in synaptic plasticity evoked by glutamate receptor activation and also by receptor tyrosine kinase (RTK) signaling. As insulin and insulin growth factor activity are dependent on tyrosine kinase receptors, we investigated whether the constitutive loss of brain cholesterol is also involved in the decay of insulin function with age. Using long-term depression (LTD) induced by application of insulin to hippocampal slices as a read-out, we found that the decline in insulin function during aging could be monitored as a progressive impairment of insulin-LTD. The application of a cholesterol inclusion complex, which donates cholesterol to the membrane and increases membrane cholesterol levels, rescued the insulin signaling deficit and insulin-LTD. In contrast, extraction of cholesterol from hippocampal neurons of adult mice produced the opposite effect. Furthermore, in vivo inhibition of Cyp46A1, an enzyme involved in brain cholesterol loss with age, improved insulin signaling. Fluorescence resonance energy transfer (FRET) experiments pointed to a change in receptor conformation by reduced membrane cholesterol, favoring ligand-independent autophosphorylation. Together, these results indicate that changes in membrane fluidity of brain cells during aging play a key role in the decay of synaptic plasticity and cognition that occurs at this late stage of life.
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http://dx.doi.org/10.1111/acel.12932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516156PMC
June 2019

The Anti-Tumor Agent Sodium Selenate Decreases Methylated PP2A, Increases GSK3βY216 Phosphorylation, Including Tau Disease Epitopes and Reduces Neuronal Excitability in SHSY-5Y Neurons.

Int J Mol Sci 2019 Feb 15;20(4). Epub 2019 Feb 15.

The Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Al Rayyan, Ad Dawḩah, Doha P.O. Box: 5825, Qatar.

Selenium application as sodium selenate was repeatedly shown to have anti-carcinogenic properties by increasing levels of the serine/ threonine protein phosphatase 2A (PP2A) in cancer cells. PP2A has a prominent role in cell development, homeostasis, and in neurons regulates excitability. PP2A, GSK3β and Tau reside together in a complex, which facilitates their interaction and (dys)-function as has been reported for several neurological disorders. In this study we recorded maximum increase in total PP2A at 3 µM sodium selenate in a neuron cell line. In conjunction with these data, whole-cell electrophysiological studies revealed that this concentration had maximum effect on membrane potentials, conductance and currents. Somewhat surprisingly, the catalytically active form, methylated PP2A (mePP2A) was significantly decreased. In close correlation to these data, the phosphorylation state of two substrate proteins, sensitive to PP2A activity, GSK3β and Tau were found to be increased. In summary, our data reveal that sodium selenate enhances PP2A levels, but reduces catalytic activity of PP2A in a dose dependent manner, which fails to reduce Tau and GSK3β phosphorylation under physiological conditions, indicating an alternative route in the rescue of cell pathology in neurological disorders.
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http://dx.doi.org/10.3390/ijms20040844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412488PMC
February 2019

Brain insulin response and peripheral metabolic changes in a Tau transgenic mouse model.

Neurobiol Dis 2019 05 19;125:14-22. Epub 2019 Jan 19.

Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc, F-59000 Lille, France; LabEx DISTALZ, F-59000 Lille, France. Electronic address:

Accumulation of hyper-phosphorylated and aggregated Tau proteins is a neuropathological hallmark of Alzheimer's Disease (AD) and Tauopathies. AD patient brains also exhibit insulin resistance. Whereas, under normal physiological conditions insulin signaling in the brain mediates plasticity and memory formation, it can also regulate peripheral energy homeostasis. Thus, in AD, brain insulin resistance affects both cognitive and metabolic changes described in these patients. While a role of Aβ oligomers and APOE4 towards the development of brain insulin resistance emerged, contribution of Tau pathology has been largely overlooked. Our recent data demonstrated that one of the physiological function of Tau is to sustain brain insulin signaling. We postulated that under pathological conditions, hyper-phosphorylated/aggregated Tau is likely to lose this function and to favor the development of brain insulin resistance. This hypothesis was substantiated by observations from patient brains with pure Tauopathies. To address the potential link between Tau pathology and brain insulin resistance, we have evaluated the brain response to insulin in a transgenic mouse model of AD-like Tau pathology (THY-Tau22). Using electrophysiological and biochemical evaluations, we surprisingly observed that, at a time when Tau pathology and cognitive deficits are overt and obvious, the hippocampus of THY-Tau22 mice exhibits enhanced response to insulin. In addition, we demonstrated that the ability of i.c.v. insulin to promote body weight loss is enhanced in THY-Tau22 mice. In line with this, THY-Tau22 mice exhibited a lower body weight gain, hypoleptinemia and hypoinsulinemia and finally a metabolic resistance to high-fat diet. The present data highlight that the brain of transgenic Tau mice exhibit enhanced brain response to insulin. Whether these observations are ascribed to the development of Tau pathology, and therefore relevant to human Tauopathies, or unexpectedly results from the Tau transgene overexpression is debatable and discussed.
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http://dx.doi.org/10.1016/j.nbd.2019.01.008DOI Listing
May 2019

AMP-Activated Protein Kinase Is Essential for the Maintenance of Energy Levels during Synaptic Activation.

iScience 2018 Nov 12;9:1-13. Epub 2018 Oct 12.

Univ. Lille, Inserm, CHU-Lille, UMR-S1172, Jean-Pierre Aubert Research Centre, Bâtiment Biserte, Place de Verdun, Lille 59045, France. Electronic address:

Although the brain accounts for only 2% of the total body mass, it consumes the most energy. Neuronal metabolism is tightly controlled, but it remains poorly understood how neurons meet their energy demands to sustain synaptic transmission. Here we provide evidence that AMP-activated protein kinase (AMPK) is pivotal to sustain neuronal energy levels upon synaptic activation by adapting the rate of glycolysis and mitochondrial respiration. Furthermore, this metabolic plasticity is required for the expression of immediate-early genes, synaptic plasticity, and memory formation. Important in this context, in neurodegenerative disorders such as Alzheimer disease, dysregulation of AMPK impairs the metabolic response to synaptic activation and processes that are central to neuronal plasticity. Altogether, our data provide proof of concept that AMPK is an essential player in the regulation of neuroenergetic metabolic plasticity induced in response to synaptic activation and that its deregulation might lead to cognitive impairments.
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http://dx.doi.org/10.1016/j.isci.2018.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203244PMC
November 2018

Fourier-Transform Infrared Imaging Spectroscopy and Laser Ablation -ICPMS New Vistas for Biochemical Analyses of Ischemic Stroke in Rat Brain.

Front Neurosci 2018 19;12:647. Epub 2018 Sep 19.

Department of Chemistry and Earth Sciences, Qatar University, Doha, Qatar.

Stroke is the main cause of adult disability in the world, leaving more than half of the patients dependent on daily assistance. Understanding the post-stroke biochemical and molecular changes are critical for patient survival and stroke management. The aim of this work was to investigate the photo-thrombotic ischemic stroke in male rats with particular focus on biochemical and elemental changes in the primary stroke lesion in the somatosensory cortex and surrounding areas, including the corpus callosum. FT-IR imaging spectroscopy and LA-ICPMS techniques examined stroke brain samples, which were compared with standard immunohistochemistry studies. The FTIR results revealed that in the lesioned gray matter the relative distribution of lipid, lipid acyl and protein contents decreased significantly. Also at this locus, there was a significant increase in aggregated protein as detected by high-levels Aβ. Areas close to the stroke focus experienced decrease in the lipid and lipid acyl contents associated with an increase in lipid ester, olefin, and methyl bio-contents with a novel finding of Aβ in the PL-GM and L-WM. Elemental analyses realized major changes in the different brain structures that may underscore functionality. In conclusion, FTIR bio-spectroscopy is a non-destructive, rapid, and a refined technique to characterize oxidative stress markers associated with lipid degradation and protein denaturation not characterized by routine approaches. This technique may expedite research into stroke and offer new approaches for neurodegenerative disorders. The results suggest that a good therapeutic strategy should include a mechanism that provides protective effect from brain swelling (edema) and neurotoxicity by scavenging the lipid peroxidation end products.
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http://dx.doi.org/10.3389/fnins.2018.00647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157330PMC
September 2018

Reversal of memory and neuropsychiatric symptoms and reduced tau pathology by selenium in 3xTg-AD mice.

Sci Rep 2018 04 24;8(1):6431. Epub 2018 Apr 24.

Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Bellaterra, 08193, Spain.

Accumulation of amyloid-β plaques and tau contribute to the pathogenesis of Alzheimer's disease (AD), but it is unclear whether targeting tau pathology by antioxidants independently of amyloid-β causes beneficial effects on memory and neuropsychiatric symptoms. Selenium, an essential antioxidant element reduced in the aging brain, prevents development of neuropathology in AD transgenic mice at early disease stages. The therapeutic potential of selenium for ameliorating or reversing neuropsychiatric and cognitive behavioral symptoms at late AD stages is largely unknown. Here, we evaluated the effects of chronic dietary sodium selenate supplementation for 4 months in female 3xTg-AD mice at 12-14 months of age. Chronic sodium selenate treatment efficiently reversed hippocampal-dependent learning and memory impairments, and behavior- and neuropsychiatric-like symptoms in old female 3xTg-AD mice. Selenium significantly decreased the number of aggregated tau-positive neurons and astrogliosis, without globally affecting amyloid plaques, in the hippocampus of 3xTg-AD mice. These results indicate that selenium treatment reverses AD-like memory and neuropsychiatric symptoms by a mechanism involving reduction of aggregated tau and/or reactive astrocytes but not amyloid pathology. These results suggest that sodium selenate could be part of a combined therapeutic approach for the treatment of memory and neuropsychiatric symptoms in advanced AD stages.
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http://dx.doi.org/10.1038/s41598-018-24741-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915484PMC
April 2018

Diclofenac 1,3,4-Oxadiazole Derivatives; Biology-Oriented Drug Synthesis (BIODS) in Search of Better Non-Steroidal, Non-Acid Antiinflammatory Agents.

Med Chem 2018 ;14(7):674-687

PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi-75280, Pakistan.

Background: Inflammation is defined as the response of immune system cells to damaged or injured tissues. The major symptoms of inflammation include increased blood flow, cellular influx, edema, elevated cellular metabolism, reactive oxygen species (ROS) nitric oxide (NO) and vasodilation. This normally protective mechanism against harmful agents when this normal mechanism becomes dysregulated that can cause serious illnesses including ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis, sepsis, and chronic pulmonary inflammation.

Method: In this study synthetic transformations on diclofenac were carried out in search of better non-steroidal antiinflammatory drugs (NSAIDs), non-acidic, antiinflammatory agents. For this purpose diclofenac derivatives (2-20) were synthesized from diclofenac (1). All derivatives (2-20) and parent diclofenac (1) were evaluated for their antiinflammatory effect using different parameters including suppression of intracellular reactive oxygen species (ROS), produced by whole blood phagocytes, produced by neutrophils, and inhibition of nitric oxide (NO) production from J774.2 macrophages. The most active compound also evaluated for cytotoxicity activity.

Results: Diclofenac (1) inhibited the ROS with an IC50 of 3.9 ± 2.8, 1.2 ± 0.0 µg/mL respectively and inhibited NO with an IC50 of 30.01 ± 0.01 µg/mL. Among its derivatives 4, 5, 11, 16, and 20, showed better antiinflammatory potential. The compound 5 was found to be the most potent inhibitor of intracellular ROS as well as NO with IC50 values of 1.9 ± 0.9, 1.7 ± 0.4 µg/mL respectively and 7.13 ± 1.0 µg/mL, respectively, and showed good inhibitory activity than parent diclofenac. The most active compounds were tested for their toxic effect on NIH-3T3 cells where all compounds were found to be non-toxic compared to the standard cytotoxic drug cyclohexamide.

Conclusion: Five derivatives were found to be active. Compound 5 was found to be the most potent inhibitor of ROS and NO compared to parent diclofenac 1 and standard drugs ibuprofen and L-NMMA, respectively. The most active compounds 1, 4, 5, 11 and 20 were found to be non-toxic on NIH-3T3 cells. Compound 4, 5, and 20 also showed good antiinflammatory potential, compound 11 and 16 showed moderate and low level of inhibition, respectively.
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http://dx.doi.org/10.2174/1573406414666180321141555DOI Listing
October 2018

Single mild traumatic brain injury results in transiently impaired spatial long-term memory and altered search strategies.

Behav Brain Res 2019 06 27;365:222-230. Epub 2018 Feb 27.

KU Leuven, Faculty of Psychology & Educational Sciences, Laboratory of Biological Psychology, Tiensestraat 102 box 3714, Leuven B-3000, Belgium.

Mild traumatic brain injury (mTBI) can lead to diffuse neurophysical damage as well as cognitive and affective alterations. The nature and extent of behavioral changes after mTBI are still poorly understood and how strong an impact force has to be to cause long-term behavioral changes is not yet known. Here, we examined spatial learning acquisition, retention and reversal in a Morris water maze, and assessed search strategies during task performance after a single, mild, closed-skull traumatic impact referred to as "minimal" TBI. Additionally, we investigated changes in conditioned learning in a contextual fear-conditioning paradigm. Results show transient deficits in spatial memory retention, which, although limited, are indicative of deficits in long-term memory reconsolidation. Interestingly, minimal TBI causes animals to relapse to less effective search strategies, affecting performance after a retention pause. Apart from cognitive deficits, results yielded a sub-acute, transient increase in freezing response after fear conditioning, with no increase in baseline behavior, an indication of a stronger affective reaction to aversive stimuli after minimal TBI or greater susceptibility to stress. Furthermore, western blot analysis showed a short-term increase in hippocampal GFAP expression, most likely indicating astrogliosis, which is typically related to injuries of the central nervous system. Our findings provide evidence that even a very mild impact to the skull can have detectable consequences on the molecular, cognitive and affective-like level. However, these effects seemed to be very transient and reversible.
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http://dx.doi.org/10.1016/j.bbr.2018.02.040DOI Listing
June 2019

High fat diet treatment impairs hippocampal long-term potentiation without alterations of the core neuropathological features of Alzheimer disease.

Neurobiol Dis 2018 05 7;113:82-96. Epub 2018 Feb 7.

Centro de Biologıa Molecular 'Severo Ochoa' (CSIC/UAM), Madrid, Spain. Electronic address:

Type 2 diabetes (T2DM) and obesity might increase the risk for AD by 2-fold. Different attempts to model the effect of diet-induced diabetes on AD pathology in transgenic animal models, resulted in opposite conclusions. Here, we used a novel knock-in mouse model for AD, which, differently from other models, does not overexpress any proteins. Long-term high fat diet treatment triggers a reduction in hippocampal N-acetyl-aspartate/myo-inositol metabolites ratio and impairs long term potentiation in hippocampal acute slices. Interestingly, these alterations do not correlate with changes in the core neuropathological features of AD, i.e. amyloidosis and Tau hyperphosphorylation. The data suggest that AD phenotypes associated with high fat diet treatment seen in other models for AD might be exacerbated because of the overexpressing systems used to study the effects of familial AD mutations. Our work supports the increasing insight that knock-in mice might be more relevant models to study the link between metabolic disorders and AD.
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http://dx.doi.org/10.1016/j.nbd.2018.02.001DOI Listing
May 2018

Tau deletion promotes brain insulin resistance.

J Exp Med 2017 Aug 26;214(8):2257-2269. Epub 2017 Jun 26.

Université de Lille, Institut National de la Santé et de la Recherche Medicale (INSERM), CHU Lille, UMR-S 1172 JPArc, Lille, France

The molecular pathways underlying tau pathology-induced synaptic/cognitive deficits and neurodegeneration are poorly understood. One prevalent hypothesis is that hyperphosphorylation, misfolding, and fibrillization of tau impair synaptic plasticity and cause degeneration. However, tau pathology may also result in the loss of specific physiological tau functions, which are largely unknown but could contribute to neuronal dysfunction. In the present study, we uncovered a novel function of tau in its ability to regulate brain insulin signaling. We found that tau deletion leads to an impaired hippocampal response to insulin, caused by altered IRS-1 and PTEN (phosphatase and tensin homologue on chromosome 10) activities. Our data also demonstrate that tau knockout mice exhibit an impaired hypothalamic anorexigenic effect of insulin that is associated with energy metabolism alterations. Consistently, we found that tau haplotypes are associated with glycemic traits in humans. The present data have far-reaching clinical implications and raise the hypothesis that pathophysiological tau loss-of-function favors brain insulin resistance, which is instrumental for cognitive and metabolic impairments in Alzheimer's disease patients.
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http://dx.doi.org/10.1084/jem.20161731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551570PMC
August 2017

Separate Ionotropic and Metabotropic Glutamate Receptor Functions in Depotentiation vs. LTP: A Distinct Role for Group1 mGluR Subtypes and NMDARs.

Front Cell Neurosci 2016 7;10:252. Epub 2016 Nov 7.

Laboratory of Biological Psychology, KU Leuven Leuven, Belgium.

Depotentiation (DP) is a mechanism by which synapses that have recently undergone long-term potentiation (LTP) can reverse their synaptic strengthening within a short time-window after LTP induction. Group 1 metabotropic glutamate receptors (mGluRs) were shown to be involved in different forms of LTP and long-term depression (LTD), but little is known about their roles in DP. Here, we generated DP by applying low-frequency stimulation (LFS) at 5 Hz after LTP had been induced by a single train of theta-burst-stimulation (TBS). While application of LFS for 2 min (DP2') generated only a short-lasting DP that was independent of the activation of -methyl-D-aspartate receptors (NMDARs) and group 1 mGluRs, LFS given for 8 min (DP8') induced a robust DP that was maintained for at least 2 h. This strong form of DP was contingent on NMDAR activation. Interestingly, DP8' appears to include a metabotropic NMDAR function because it was blocked by the competitive NMDAR antagonist D-AP5 but not by the use-dependent inhibitor MK-801 or high Mg. Furthermore, DP8' was enhanced by application of the mGluR1 antagonist (YM 298198, 1 μM). The mGluR5 antagonist 2-Methyl-6(phenylethynyl) pyridine (MPEP, 40 μM), in contrast, failed to affect it. The induction of LTP, in turn, was NMDAR dependent (as tested with D-AP5), and blocked by MPEP but not by YM 298198. These results indicate a functional dissociation of mGluR1 and mGluR5 in two related and consecutively induced types of NMDAR-dependent synaptic plasticity (LTP → DP) with far-reaching consequences for their role in plasticity and learning under normal and pathological conditions.
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http://dx.doi.org/10.3389/fncel.2016.00252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098392PMC
November 2016

Quinolinic acid injection in mouse medial prefrontal cortex affects reversal learning abilities, cortical connectivity and hippocampal synaptic plasticity.

Sci Rep 2016 11 7;6:36489. Epub 2016 Nov 7.

Laboratory of Biological Psychology, Brain and Cognition, KU Leuven, Tiensestraat 102, 3000 Leuven, Belgium.

Intracerebral injection of the excitotoxic, endogenous tryptophan metabolite, quinolinic acid (QA), constitutes a chemical model of neurodegenerative brain disease. Complementary techniques were combined to examine the consequences of QA injection into medial prefrontal cortex (mPFC) of C57BL6 mice. In accordance with the NMDAR-mediated synapto- and neurotoxic action of QA, we found an initial increase in excitability and an augmentation of hippocampal long-term potentiation, converting within two weeks into a reduction and impairment, respectively, of these processes. QA-induced mPFC excitotoxicity impaired behavioral flexibility in a reversal variant of the hidden-platform Morris water maze (MWM), whereas regular, extended MWM training was unaffected. QA-induced mPFC damage specifically affected the spatial-cognitive strategies that mice use to locate the platform during reversal learning. These behavioral and cognitive defects coincided with changes in cortical functional connectivity (FC) and hippocampal neuroplasticity. FC between various cortical regions was assessed by resting-state fMRI (rsfMRI) methodology, and mice that had received QA injection into mPFC showed increased FC between various cortical regions. mPFC and hippocampus (HC) are anatomically as well as functionally linked as part of a cortical network that controls higher-order cognitive functions. Together, these observations demonstrate the central functional importance of rodent mPFC as well as the validity of QA-induced mPFC damage as a preclinical rodent model of the early stages of neurodegeneration.
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http://dx.doi.org/10.1038/srep36489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098239PMC
November 2016

Aging Triggers a Repressive Chromatin State at Bdnf Promoters in Hippocampal Neurons.

Cell Rep 2016 09;16(11):2889-2900

Centro Biología Molecular Severo Ochoa, CSIC-UAM, 28049 Madrid, Spain. Electronic address:

Cognitive capacities decline with age, an event accompanied by the altered transcription of synaptic plasticity genes. Here, we show that the transcriptional induction of Bdnf by a mnemonic stimulus is impaired in aged hippocampal neurons. Mechanistically, this defect is due to reduced NMDA receptor (NMDAR)-mediated activation of CaMKII. Decreased NMDAR signaling prevents changes associated with activation at specific Bdnf promoters, including displacement of histone deacetylase 4, recruitment of the histone acetyltransferase CBP, increased H3K27 acetylation, and reduced H3K27 trimethylation. The decrease in NMDA-CaMKII signaling arises from constitutive reduction of synaptic cholesterol that occurs with normal aging. Increasing the levels of neuronal cholesterol in aged neurons in vitro, ex vivo, and in vivo restored NMDA-induced Bdnf expression and chromatin remodeling. Furthermore, pharmacological prevention of age-associated cholesterol reduction rescued signaling and cognitive deficits of aged mice. Thus, reducing hippocampal cholesterol loss may represent a therapeutic approach to reverse cognitive decline during aging.
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http://dx.doi.org/10.1016/j.celrep.2016.08.028DOI Listing
September 2016

Genetically Induced Retrograde Amnesia of Associative Memories After Neuroplastin Ablation.

Biol Psychiatry 2017 01 11;81(2):124-135. Epub 2016 Apr 11.

Neurogenetics Special Laboratory, Leibniz Institute for Neurobiology, Magdeburg, Germany. Electronic address:

Background: Neuroplastin cell recognition molecules have been implicated in synaptic plasticity. Polymorphisms in the regulatory region of the human neuroplastin gene (NPTN) are correlated with cortical thickness and intellectual abilities in adolescents and in individuals with schizophrenia.

Methods: We characterized behavioral and functional changes in inducible conditional neuroplastin-deficient mice.

Results: We demonstrate that neuroplastins are required for associative learning in conditioning paradigms, e.g., two-way active avoidance and fear conditioning. Retrograde amnesia of learned associative memories is elicited by inducible neuron-specific ablation of Nptn gene expression in adult mice, which shows that neuroplastins are indispensable for the availability of previously acquired associative memories. Using single-photon emission computed tomography imaging in awake mice, we identified brain structures activated during memory recall. Constitutive neuroplastin deficiency or Nptn gene ablation in adult mice causes substantial electrophysiologic deficits such as reduced long-term potentiation. In addition, neuroplastin-deficient mice reveal profound physiologic and behavioral deficits, some of which are related to depression and schizophrenia, which illustrate neuroplastin's essential functions.

Conclusions: Neuroplastins are essential for learning and memory. Retrograde amnesia after an associative learning task can be induced by ablation of the neuroplastin gene. The inducible neuroplastin-deficient mouse model provides a new and unique means to analyze the molecular and cellular mechanisms underlying retrograde amnesia and memory.
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http://dx.doi.org/10.1016/j.biopsych.2016.03.2107DOI Listing
January 2017

TRPM4-dependent post-synaptic depolarization is essential for the induction of NMDA receptor-dependent LTP in CA1 hippocampal neurons.

Pflugers Arch 2016 Apr 3;468(4):593-607. Epub 2015 Dec 3.

Laboratory of Biological Psychology, University of Leuven, Tiensestraat 102, 3000, Leuven, Belgium.

TRPM4 is a calcium-activated but calcium-impermeable non-selective cation (CAN) channel. Previous studies have shown that TRPM4 is an important regulator of Ca(2+)-dependent changes in membrane potential in excitable and non-excitable cell types. However, its physiological significance in neurons of the central nervous system remained unclear. Here, we report that TRPM4 proteins form a CAN channel in CA1 neurons of the hippocampus and we show that TRPM4 is an essential co-activator of N-methyl-D-aspartate (NMDA) receptors (NMDAR) during the induction of long-term potentiation (LTP). Disrupting the Trpm4 gene in mice specifically eliminates NMDAR-dependent LTP, while basal synaptic transmission, short-term plasticity, and NMDAR-dependent long-term depression are unchanged. The induction of LTP in Trpm4 (-/-) neurons was rescued by facilitating NMDA receptor activation or post-synaptic membrane depolarization. Accordingly, we obtained normal LTP in Trpm4 (-/-) neurons in a pairing protocol, where post-synaptic depolarization was applied in parallel to pre-synaptic stimulation. Taken together, our data are consistent with a novel model of LTP induction in CA1 hippocampal neurons, in which TRPM4 is an essential player in a feed-forward loop that generates the post-synaptic membrane depolarization which is necessary to fully activate NMDA receptors during the induction of LTP but which is dispensable for the induction of long-term depression (LTD). These results have important implications for the understanding of the induction process of LTP and the development of nootropic medication.
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http://dx.doi.org/10.1007/s00424-015-1764-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792339PMC
April 2016

Nxf7 deficiency impairs social exploration and spatio-cognitive abilities as well as hippocampal synaptic plasticity in mice.

Front Behav Neurosci 2015 10;9:179. Epub 2015 Jul 10.

Laboratory of Biological Psychology, University of Leuven, KU Leuven Leuven, Belgium.

Nuclear RNA export factors (NXF) are conserved in all metazoans and are deemed essential for shuttling RNA across the nuclear envelope and other post-transcriptional processes (such as mRNA metabolism, storage and stability). Disruption of human NXF5 has been implicated in intellectual and psychosocial disabilities. In the present report, we use recently described Nxf7 knockout (KO) mice as an experimental model to analyze in detail the behavioral consequences of clinical NXF5 deficiency. We examined male Nxf7 KO mice using an extended cognitive and behavioral test battery, and recorded extracellular field potentials in the hippocampal CA1 region. We observed various cognitive and behavioral changes including alterations in social exploration, impaired spatial learning and spatio-cognitive abilities. We also defined a new experimental paradigm to discriminate search strategies in Morris water maze and showed significant differences between Nxf7 KO and control animals. Furthermore, while we observed no difference in a nose poke suppression in an conditioned emotional response (CER) protocol, Nxf7 KO mice were impaired in discriminating between differentially reinforced cues in an auditory fear conditioning protocol. This distinct neurocognitive phenotype was accompanied by impaired hippocampal Long-term potentiation (LTP), while long-term depression (LTD) was not affected by Nxf7 deficiency. Our data demonstrate that disruption of murine Nxf7 leads to behavioral phenotypes that may relate to the intellectual and social deficits in patients with NXF5 deficiency.
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http://dx.doi.org/10.3389/fnbeh.2015.00179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498129PMC
July 2015

Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome.

Neuron 2015 Jul;87(2):382-98

Center for Human Genetics and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium; VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy. Electronic address:

The Fragile X mental retardation protein (FMRP) regulates neuronal RNA metabolism, and its absence or mutations leads to the Fragile X syndrome (FXS). The β-amyloid precursor protein (APP) is involved in Alzheimer's disease, plays a role in synapse formation, and is upregulated in intellectual disabilities. Here, we show that during mouse synaptogenesis and in human FXS fibroblasts, a dual dysregulation of APP and the α-secretase ADAM10 leads to the production of an excess of soluble APPα (sAPPα). In FXS, sAPPα signals through the metabotropic receptor that, activating the MAP kinase pathway, leads to synaptic and behavioral deficits. Modulation of ADAM10 activity in FXS reduces sAPPα levels, restoring translational control, synaptic morphology, and behavioral plasticity. Thus, proper control of ADAM10-mediated APP processing during a specific developmental postnatal stage is crucial for healthy spine formation and function(s). Downregulation of ADAM10 activity at synapses may be an effective strategy for ameliorating FXS phenotypes.
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http://dx.doi.org/10.1016/j.neuron.2015.06.032DOI Listing
July 2015

Rescue of impaired late-phase long-term depression in a tau transgenic mouse model.

Neurobiol Aging 2015 Feb 28;36(2):730-9. Epub 2014 Sep 28.

Laboratory of Biological Psychology, University of Leuven, Leuven, Belgium. Electronic address:

Cognitive decline, the hallmark of Alzheimer's disease, and accompanying neuropsychiatric symptoms share dysfunctions of synaptic processes as a common cellular pathomechanism. Long-term potentiation has proven to be a sensitive tool for the "diagnosis" of such synaptic dysfunctions. Much less, however, is known about how long-term depression (LTD), an alternative mechanism for the storage of memory, is affected by Alzheimer's disease progression. Here, we demonstrate that impaired late LTD (>3 hours) in THY-Tau22 mice can be rescued by either inhibition of glycogen synthase kinase-3 (GSK3β) activity or by application of the protein-phosphatase 2A agonist selenate. In line with these findings, we observed increased phosphorylation of GSK3β at Y216 and reduced total phosphatase activity in biochemical assays of hippocampal tissue of THY-Tau22 mice. Interestingly, LTD induction and pharmacologic inhibition of GSK3β appeared to downregulate GSK3ß activity via a marked upregulation of phosphorylation at the inhibitory Ser9 residue. Our results point to alterations in phosphorylation and/or dephosphorylation homeostasis as key mechanisms underlying the deficits in LTD and hippocampus-dependent learning found in THY-Tau22 mice.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.09.015DOI Listing
February 2015

Cognition and hippocampal synaptic plasticity in mice with a homozygous tau deletion.

Neurobiol Aging 2014 Nov 10;35(11):2474-2478. Epub 2014 May 10.

Laboratory of Biological Psychology, Catholic University of Leuven, Belgium. Electronic address:

Tau has been implicated in the organization, stabilization, and dynamics of microtubules. In Alzheimer's disease and more than 20 neurologic disorders tau missorting, hyperphosphorylation, and aggregation is a hallmark. They are collectively referred to as tauopathies. Although the impact of human tauopathies on cognitive processes has been explored in transgenic mouse models, the functional consequences of tau deletion on cognition are far less investigated. Here, we subjected tau knock-out (KO) mice to a battery of neurocognitive, behavioral, and electrophysiological tests. Although KO and wild-type mice were indistinguishable in motor abilities, exploratory and anxiety behavior, KO mice showed impaired contextual and cued fear conditioning. In contrast, extensive spatial learning in the water maze resulted in better performance of KO mice during acquisition. In electrophysiological experiments, basal synaptic transmission and paired-pulse facilitation in the hippocampal CA1-region were unchanged. Interestingly, deletion of tau resulted in severe deficits in long-term potentiation but not long-term depression. Our results suggest a role of tau in certain cognitive functions and implicate long-term potentiation as the relevant physiological substrate.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.05.005DOI Listing
November 2014
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