Publications by authors named "Zareen Amtul"

36 Publications

Engineering of fluorescent or photoactive Trojan probes for detection and eradication of β-Amyloids.

Drug Deliv 2020 Dec;27(1):917-926

Department of Chemistry and Biochemistry, University of Windsor, Windsor, Canada.

Trojan horse technology institutes a potentially promising strategy to bring together a diagnostic or cell-based drug design and a delivery platform. It provides the opportunity to re-engineer a novel multimodal, neurovascular detection probe, or medicine to fuse with blood-brain barrier (BBB) molecular Trojan horse. In Alzheimer's disease (AD) this could allow the targeted delivery of detection or therapeutic probes across the BBB to the sites of plaques and tangles development to image or decrease amyloid load, enhance perivascular Aβ clearance, and improve cerebral blood flow, owing principally to the significantly improved cerebral permeation. A Trojan horse can also be equipped with photosensitizers, nanoparticles, quantum dots, or fluorescent molecules to function as multiple targeting theranostic compounds that could be activated following changes in disease-specific processes of the diseased tissue such as pH and protease activity, or exogenous stimuli such as, light. This concept review theorizes the use of receptor-mediated transport-based platforms to transform such novel ideas to engineer systemic and smart Trojan detection or therapeutic probes to advance the neurodegenerative field.
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http://dx.doi.org/10.1080/10717544.2020.1785048DOI Listing
December 2020

Differential temporal and spatial post-injury alterations in cerebral cell morphology and viability.

J Comp Neurol 2021 Feb 28;529(2):421-433. Epub 2020 Jun 28.

Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Canada.

Combination of ischemia and β-amyloid (Aβ) toxicity has been shown to simultaneously increase neuro-inflammation, endogenous Aβ deposition, and neurodegeneration. However, studies on the evolution of infarct and panorama of cellular degeneration as a synergistic or overlapping mechanism between ischemia and Aβ toxicity are lacking. Here, we compared fluorojade B (FJB) and hematoxylin and eosin (H&E) stains primarily to examine the chronology of infarct, and the viability and morphological changes in neuroglia and neurons located in different brain regions on d1, d7, and d28 post Aβ toxicity and endothelin-1 induced ischemia (ET1) in rats. We demonstrated a regional difference in cellular degeneration between cortex, corpus callosum, striatum, globus pallidus, and thalamus after cerebral injury. Glial cells in the cortex and corpus callosum underwent delayed FJB staining from d7 to d28, but neurons in cortex disappeared within the first week of cerebral injury. Striatal lesion core and globus pallidus of Aβ + ET1 rats showed extensive degeneration of neuronal cells compared with ET1 rats alone starting from d1. Differential and exacerbated expressions of cyclooxygenase-2 might be the cause of excessive neuronal demise in the striatum of Aβ + ET1 rats. Such an investigation may improve our understanding to identify and manipulate a critical therapeutic window post comorbid injury.
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http://dx.doi.org/10.1002/cne.24955DOI Listing
February 2021

Correction to: Role of Delayed Neuroglial Activation in Impaired Cerebral Blood Flow Restoration Following Comorbid Injury.

Cell Mol Neurobiol 2020 04;40(3):381-382

Department of Pathology and Laboratory Medicine, University of Western Ontario, London, N6A 5C1, Canada.

The original version of this article contained a random order of part labels for Fig. 4. The correct caption of Fig. 4 with correct order of part labels is given below.
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http://dx.doi.org/10.1007/s10571-019-00739-8DOI Listing
April 2020

Developing Trojan horses to induce, diagnose and suppress Alzheimer's pathology.

Pharmacol Res 2019 11 4;149:104471. Epub 2019 Oct 4.

Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan. Electronic address:

There are many obstacles impeding the Alzheimer's disease (AD) research. For instance, its early diagnosis to identify individuals at risk has not been successful so far. AD animal models cannot be created without genetic pre-disposition or surgical manipulation. Single gene/protein delivery has so far failed to achieve significant clinical improvements in multifactorial AD. We hypothesize that the blood-brain barrier (BBB) penetration issues are the major obstacle in the development of current Alzheimer's causative, diagnostic, and multi-targeted therapeutic probes, and partly the cause of the failure of more than 99% of intervention trials. To overcome this problem, shuttle peptides or monoclonal antibodies for receptors on BBB can act as molecular Trojan horses to transport the fused novel classes of re-engineered AD causative agents, diagnostic probes, or multiple function neurovascular medicines across the BBB via receptor-mediated transport to cause, diagnose, or improve the AD phenotype, respectively. Here, we propose the design of such Trojan horses, comprising three essential components that could (i) reverse Aβ amyloidosis, (ii) clear liberated Aβ, and (iii) improve angiogenesis or endothelial metabolic dysfunction, besides alleviating the inflammation, to eventually enhance neuronal health, cerebral blood flow, and cognitive function. Such Trojan horses can aid in AD research by diagnosing Aβ-oligomers at earlier stages, creating improved animal models by exposing transgenic animals to amyloid-inducing agents, and allowing treatment by novel neurovascular medicines.
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http://dx.doi.org/10.1016/j.phrs.2019.104471DOI Listing
November 2019

Role of Delayed Neuroglial Activation in Impaired Cerebral Blood Flow Restoration Following Comorbid Injury.

Cell Mol Neurobiol 2020 Apr 14;40(3):369-380. Epub 2019 Sep 14.

Department of Pathology and Laboratory Medicine, University of Western Ontario, London, N6A 5C1, Canada.

Besides other causes, ischemia and Alzheimer's disease pathology is also linked to decreased cerebral blood flow (CBF). There is little or no consensus about the role of neuroglial cells in maintaining CBF in various neuropathologies. This consensus becomes scarcer when it comes to clinical and experimental cases of comorbid Abeta-amyloid (Aβ) toxicity and ischemia. Here, a comorbid rat model of Aβ toxicity and endothelin-1 induced ischemia (ET1) not only demonstrated the appearance of axotomized phagocytosed pyknotic neurons (NeuN) immediately after the injury, but also showed a diversity of continuously changing neuroglia (MHC Class II/OX6, Iba1) and macrophage (Iba1/CD68) phenotypes with round, stout somas, and retracted processes. This is indicative of a response to a concomitant increase in large fluid-filled spaces due to the vascular leakage. Ironically 4 weeks after the injury despite a conclusive reduction in neurons, CBF restoration in ET1 rats was associated with a massive increase in neuroglial cell numbers, hypertrophy, ramification, and soma sizes bordering the continuously reducing lesion core and inflamed vasculature, possibly to shield their leaky phenotype. Astrocytes were also found to be releasing matrix metalloproteinase9 (MMP9), which stabilized matrix ligand β-dystroglycan (β-DG) in repaired or functional vessels. Changing neuroglia phenotypes, responses, motility, astrocytic recruitment of MMP9, and β-DG stabilization implies the role of communication between neuroglia and endothelium in recovering CBF, in the absence of neurons, in ET1 rats compared to Aβ+ET1 rats, which showed characteristics delayed neuroglial activation. Stimulation of timely neuroglial reactivity may serve as a viable strategy to compensate for the neuronal loss in restoring CBF in comorbid cases of ischemia and Aβ toxicity.
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http://dx.doi.org/10.1007/s10571-019-00735-yDOI Listing
April 2020

The spatial cerebral damage caused by larger infarct and β-amyloid toxicity is driven by the anatomical/functional connectivity.

J Comp Neurol 2020 01 19;528(1):48-60. Epub 2019 Jul 19.

Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Ontario, Canada.

Large cerebral infarctions are major predictors of death and severe disability from stroke. Conversely, data concerning these types of infarctions and the affected adjacent brain circuits are scarce. It remains to be determined if the co-morbid concurrence of large infarct and β-amyloid (Aβ) toxicity can precipitate the early development of dementia. Here, we described a dose-dependent effect of a unilateral striatal injection of vasoconstrictive endothelin-1 (ET-1) along with Aβ toxicity on CNS pathogenesis; driven by the anatomical and functional networks within a brain circuit. After 21 days of treatment, a high dose (60 pmol) of ET-1 (E60) alone caused the greatest increase in neuroinflammation, mainly in the ipsilateral striatum and distant regions with synaptic links to the striatal lesion such as white matter (subcortical white matter, corpus callosum, internal capsule, anterior commissure), gray matter (globus pallidus, thalamus), and cortices (cingulate, motor, somatosensory, entorhinal). The combined E60 + Aβ treatment also extended perturbation in the contralateral hemisphere of these rats, such as increased deposition of amyloid precursor protein fragments associated with the appearance of degenerating cells and the leakage of laminin from the basement membrane across a compromised blood-brain barrier. However, the cerebral damage induced by the 6 pmol ET-1 (E6), Aβ and E6 + Aβ rats was not detrimental enough to injure the complete network. The appreciation of the causal interactions among distinct anatomical units in the brain after ischemia and Aβ toxicity will help in the design of effective and alternative therapeutics that may disassociate the synergistic or additive association between the infarcts and Aβ toxicity.
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http://dx.doi.org/10.1002/cne.24738DOI Listing
January 2020

Pathological Changes in Microvascular Morphology, Density, Size and Responses Following Comorbid Cerebral Injury.

Front Aging Neurosci 2019 27;11:47. Epub 2019 Mar 27.

Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada.

Aberrations in brain microcirculation and the associated increase in blood-brain-barrier (BBB) permeability in addition to neuroinflammation and Aβ deposition observed in Alzheimer's disease (AD) and ischemia have gained considerable attention recently. However, the role of microvascular homeostasis as a pathogenic substrate to disturbed microperfusion as well as an overlapping etiologic mechanism between AD and ischemia has not been thoroughly explored. In this study, we employ temporal histopathology of cerebral vasculature in a rat model of β-amyloid (Aβ) toxicity and endothelin-1 induced-ischemia (ET1) to investigate the panorama of cerebral pathology and the protein expression on d1, d7, and d28 post-injury. The combination of Aβ and ET1 pathological states leads to an alteration in microvascular anatomy, texture, diameter, density, and protein expression, in addition to disturbed vessel-matrix-connections, inter-compartmental water exchange and basement membrane profile within the lesion epicenter localized in the striatum of Aβ+ET1 brains compared to Aβ and ET1 rats. We conclude that the neural microvascular network, in addition to the neural tissue, is not only sensitive to structural deterioration but also serves as an underlying vascular etiology between ischemia and AD pathologies. Such investigation can provide prospects to appreciate the interrelationships between structure and responses of cerebral microvasculature and to provide a venue for vascular remodeling as a new treatment strategy.
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http://dx.doi.org/10.3389/fnagi.2019.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445844PMC
March 2019

Characteristics and Outcome of Obstetric Acute Kidney Injury in Pakistan: A Single-center Prospective Observational Study.

Cureus 2018 Sep 26;10(9):e3362. Epub 2018 Sep 26.

Nephrology, Allama Iqbal Medical College, Lahore, PAK.

Introduction Acute kidney injury (AKI) continues to be a cause of increased morbidity and mortality in pregnant women. While studies have been conducted on the incidence and etiology of this complication, the outcomes of obstetric AKI have not been extensively investigated. The primary focus of this prospective observational study was to analyze the risk factors, etiologies as well as maternal and fetal outcomes of AKI in pregnant females in Pakistan. Methods A total of 56 patients with obstetric AKI were recruited. Patients were followed for a period of three months postpartum. The diagnosis and staging of AKI were based on the classification of the Acute Kidney Injury Network (AKIN). Results Fifteen patients were lost to follow-up and were excluded from the study. The mean age of the remaining 41 patients was 26±6 years. Twenty-two (54%) patients were multigravida, and 19 (46%) were primigravida. Twenty (48%) patients did not receive any antenatal care, 13 (31%) were visited by a traditional birth attendant, and only eight (19%) had adequate antenatal care by a gynecologist. Out of 41 patients, seven (17%) presented before 28 weeks, and 34 (83%) patients presented after 28 weeks of gestation. Four (10%) patients were found to be in stage I, four (10%) in stage II, and 33 (80%) patients in stage III AKI during hospitalization. The causes of AKI included sepsis in 32 (78%), intrauterine death in 24 (60%), postpartum hemorrhage in 17 (41%), shock in 15 (36%), pre-eclampsia/eclampsia in seven (17%), and coagulopathy in three (7%) patients. Twenty-eight (68.3%) patients received hemodialysis during the hospital stay. Three-month follow-up showed complete resolution of AKI in 14 (34.2%) patients, partial resolution in seven (17%), end-stage renal disease in 10 (24.4%), and death in 10 (24.4%) patients. Conclusion The present study indicates that a vast majority of patients with obstetric AKI require dialysis. Residual renal dysfunction and end-stage renal disease were common at the three-month follow-up. Incidentally, sepsis and intrauterine death were the leading causes in this study population. Increased awareness and appropriate obstetrical care may have a significantly positive impact on decreasing the morbidity and mortality in these patients.
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http://dx.doi.org/10.7759/cureus.3362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257491PMC
September 2018

Spatial Dynamics of Vascular and Biochemical Injury in Rat Hippocampus Following Striatal Injury and Aβ Toxicity.

Mol Neurobiol 2019 Apr 28;56(4):2714-2727. Epub 2018 Jul 28.

Department of Pathology and Laboratory Medicine, University of Western Ontario, London, N6A 5C1, Canada.

The hippocampus, a brain region vital for memory and learning, is sensitive to the damage caused by ischemic/hypoxic stroke and is one of the main regions affected by Alzheimer's disease. The pathological changes that might occur in the hippocampus and its connections, because of cerebral injury in a distant brain region, such as the striatum, have not been examined. Therefore, in the present study, we evaluated the combined effects of endothelin-1-induced ischemia (ET1) in the striatum and β-amyloid (Aβ) toxicity on hippocampal pathogenesis, dictated by the anatomical and functional intra- and inter-regional hippocampal connections to the striatum. The hippocampal pathogenesis induced by Aβ or ET1 alone was not severe enough to significantly affect the entire circuit of the hippocampal network. However, the combination of the two pathological states (ET1 + Aβ) led to an exacerbated increase in neuroinflammation, deposition of the amyloid precursor protein (APP) fragments with the associated appearance of degenerating cells, and blood-brain-barrier disruption. This was observed mainly in the hippocampal formation (CA2 and CA3 regions), the dentate gyrus as well as distinct regions with synaptic links to the hippocampus such as entorhinal cortex, thalamus, and basal forebrain. In addition, ET1 + Aβ-treated rats also demonstrated protracted loss of AQP4 depolarization, dissolution of β-dystroglycan, and basement membrane laminin with associated IgG and dysferlin leakage. Spatial dynamics of hippocampal injury in ET1 + Aβ rats may provide a valuable model to study new targets for clinical therapeutic applications, specifically when areas remotely connected to hippocampus are damaged.
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http://dx.doi.org/10.1007/s12035-018-1225-3DOI Listing
April 2019

Altered Insulin/Insulin-Like Growth Factor Signaling in a Comorbid Rat model of Ischemia and β-Amyloid Toxicity.

Sci Rep 2018 03 23;8(1):5136. Epub 2018 Mar 23.

Department of Anatomy and Cell Biology, University of Western Ontario, London, N6A 5C1, Canada.

Ischemic stroke and diabetes are vascular risk factors for the development of impaired memory such as dementia and/or Alzheimer's disease. Clinical studies have demonstrated that minor striatal ischemic lesions in combination with β-amyloid (Aβ) load are critical in generating cognitive deficits. These cognitive deficits are likely to be associated with impaired insulin signaling. In this study, we examined the histological presence of insulin-like growth factor-I (IGF-1) and insulin receptor substrate (IRS-1) in anatomically distinct brain circuits compared with morphological brain damage in a co-morbid rat model of striatal ischemia (ET1) and Aβ toxicity. The results demonstrated a rapid increase in the presence of IGF-1 and IRS-1 immunoreactive cells in Aβ + ET1 rats, mainly in the ipsilateral striatum and distant regions with synaptic links to the striatal lesion. These regions included subcortical white matter, motor cortex, thalamus, dentate gyrus, septohippocampal nucleus, periventricular region and horizontal diagonal band of Broca in the basal forebrain. The alteration in IGF-1 and IRS-1 presence induced by ET1 or Aβ rats alone was not severe enough to affect the entire brain circuit. Understanding the causal or etiologic interaction between insulin and IGF signaling and co-morbidity after ischemia and Aβ toxicity will help design more effective therapeutics.
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http://dx.doi.org/10.1038/s41598-018-22985-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865153PMC
March 2018

The Dynamics of Impaired Blood-Brain Barrier Restoration in a Rat Model of Co-morbid Injury.

Mol Neurobiol 2018 Oct 5;55(10):8071-8083. Epub 2018 Mar 5.

Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, N6A 5C1, Canada.

Defect in brain microperfusion is increasingly recognized as an antecedent event to Alzheimer's disease (AD) and ischemia. Nevertheless, studies on the role of impaired microperfusion as a pathological trigger to neuroinflammation, Aβ deposition as well as blood-brain barrier (BBB) disruption, and the etiological link between AD and ischemia are lacking. In this study, we employ in vivo sequential magnetic resonance imaging (MRI) and computed tomography (CT) imaging in a co-morbid rat model of β-amyloid toxicity (Aβ) and ischemia (ET1) with subsequent histopathology of striatal lesion core and penumbra at 1, 7, and 28 days post injury. Within 24 h, cerebral injury resulted in increased BBB permeability due to the dissolution of β-dystroglycan (β-DG) and basement membrane laminin by active matrix metalloproteinase9 (MMP9). As a result, net flow of circulating IgG down a hydrostatic gradient into the parenchyma led to vasogenic edema and impaired perfusion, thus increasing the apparent hyperintensity in true fast imaging with steady-state free precession (true FISP) imaging and acute hypoperfusion in CT. This was followed by a slow recruitment of reactive astroglia to the affected brain and depolarization of aquaporin4 (AQP4) expression resulting in cytotoxic edema-in an attempt to resolve vasogenic edema. On d28, functional BBB was restored in ET1 rats as observed by astrocytic MMP9 release, β-DG stabilization, and new vessel formation. This was confirmed by reduced hyperintensity on true FISP imaging and normalized cerebral blood flow in CT. While, Aβ toxicity alone was not detrimental enough, Aβ+ET1 rats showed delayed differential expression of MMP9, late recruitment of astroglial cells, protracted loss of AQP4 depolarization, and thus delayed BBB restoration and cerebral perfusion.
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http://dx.doi.org/10.1007/s12035-018-0904-4DOI Listing
October 2018

Dipyridamole plus Triflusal versus Triflusal Alone in Infarct Reduction after Middle Cerebral Artery Occlusion.

J Stroke Cerebrovasc Dis 2018 May 12;27(5):1283-1287. Epub 2018 Jan 12.

Anatomy and Cell Biology Department, The University of Western Ontario, London, Ontario, Canada.

Background And Purpose: The objective of this work is to study the dose-dependent effect of combination therapy with dipyridamole and triflusal over that of triflusal alone on infarct size after middle cerebral artery occlusion (MCAO) ischemia.

Materials And Methods: Male Wistar rats were subjected to a permanent MCAO in the right hemisphere. Rats received triflusal alone and with dipyridamole via oral route. Three days after surgery, infarct volumes were measured.

Results: The lower dose regime of triflusal (10 mg/kg) and dipyridamole (200 mg/kg) caused the greatest decrease in infarct size compared with higher dose regime of triflusal (30 mg/kg) and dipyridamole (200 mg/kg) (P <.01), triflusal (30 mg/kg) alone (P <.07), and vehicle-treated controls.

Conclusions: The lower dose combination of dipyridamole and triflusal appears to be more effective than triflusal alone after MCAO-induced cerebral ischemia. Therefore, there is a strong rationale to continue to examine the protective effects of triflusal and dipyridamole after cerebral ischemia.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.12.013DOI Listing
May 2018

Microbial Proteins as Novel Industrial Biotechnology Hosts to Treat Epilepsy.

Mol Neurobiol 2017 12 1;54(10):8211-8224. Epub 2016 Dec 1.

Sir Wilfrid Laurier Secondary School, Thames Valley District School Board, N6C 4W7, London, ON, Canada.

Epilepsy is characterized by the hyperexcitability of various neuronal circuits that results due to the imbalance between glutamate-mediated excitation of voltage-gated cation channels and γ-amino butyric acid (GABA)-mediated inhibition of anion channels leading to aberrant, sporadic oscillations or fluctuations in neuronal electrical activity. Epilepsy with a risk of mortality and around 65 million sufferers of all ages all over the world is limited therapeutically with high rates of adverse reactions, lack of complete seizure control, and over 30% patients with refractory epilepsy. The only alternative to medicines is to identify and surgically remove the seizure foci in the brain or to abort the seizures just as they begin using an implanted cerebral electrode. However, these alternatives are unable to precisely aim aberrant neuronal circuits while leaving others unaltered. Epilepsy animal models also constitute the identical constraint. Thus, a better target-specific approach is needed to study and treat epilepsy. Unicellular green algae Chlamydomonas reinhardtii expresses a channelrhodopsin-2 (ChR2) sodium ion channel protein that controls the phototaxis movement of algae in response to blue light. Similarly, archaeon Natronomonas pharaonis (NpHR) expresses a monovalent Cl channel protein halorhodopsin that responds to yellow light. These features of ChR2 and NpHR proteins can be used in optogenetic techniques to manipulate the bi-directional firing pattern of neuronal circuits in an attempt to better understand the pathophysiology of epileptic seizures as well as to discover novel potential drugs to treat epilepsy.
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http://dx.doi.org/10.1007/s12035-016-0279-3DOI Listing
December 2017

Why therapies for Alzheimer's disease do not work: Do we have consensus over the path to follow?

Authors:
Zareen Amtul

Ageing Res Rev 2016 Jan 12;25:70-84. Epub 2015 Sep 12.

Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.

Alzheimer's disease (AD) represents a personal tragedy of enormous magnitude, which imposes a daunting worldwide challenge for health-care providers and society as well. In last five decades, global research in clinics and laboratories has illuminated many features of this sinister and eventually fatal disease. Notwithstanding this development, the Alzheimer's research apparently has come across a phase of disappointment and a little reservation about the direction to follow. Persistently distressing controversies and a significant number of missing facts shed further uncertainty about the path forward. A detailed description of some of the main controversies in AD research may assist the field towards finding a resolution. Here I reviewed some alarming concerns or controversies related to these primary issues and emphasized on a possible mechanism to settle them.
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http://dx.doi.org/10.1016/j.arr.2015.09.003DOI Listing
January 2016

Neural plasticity and memory: molecular mechanism.

Rev Neurosci 2015 ;26(3):253-68

Deciphering the cellular and molecular mechanisms of memory has been an important topic encompassing the learning and memory domain besides the neurodegenerative disorders. Synapses accumulate cognitive information from life-lasting alterations of their molecular and structural composition. Current memory storage models identify posttranslational modification imperative for short-term information storage and mRNA translation for long-term information storage. However, the precise account of these modifications has not been summarized at the individual synapse level. Therefore, herein we describe the spatiotemporal reorganization of synaptic plasticity at the dendritic spine level to elucidate the mechanism through which synaptic substructures are remodeled; though at the molecular level, such mechanisms are still quite unclear. It has thus been concluded that the existing mechanisms do not entirely elaborate memory storage processes. Further efforts are therefore encouraged to delineate the mechanism of neuronal connectivity at the chemical level as well, including inter- or intramolecular bonding patterns at the synaptic level, which may be a permissive and vital step of memory storage.
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http://dx.doi.org/10.1515/revneuro-2014-0075DOI Listing
October 2015

Neural Plasticity and Memory: Is Memory Encoded in Hydrogen Bonding Patterns?

Neuroscientist 2016 Feb 28;22(1):9-18. Epub 2014 Aug 28.

H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.

Current models of memory storage recognize posttranslational modification vital for short-term and mRNA translation for long-lasting information storage. However, at the molecular level things are quite vague. A comprehensive review of the molecular basis of short and long-lasting synaptic plasticity literature leads us to propose that the hydrogen bonding pattern at the molecular level may be a permissive, vital step of memory storage. Therefore, we propose that the pattern of hydrogen bonding network of biomolecules (glycoproteins and/or DNA template, for instance) at the synapse is the critical edifying mechanism essential for short- and long-term memories. A novel aspect of this model is that nonrandom impulsive (or unplanned) synaptic activity functions as a synchronized positive-feedback rehearsal mechanism by revising the configurations of the hydrogen bonding network by tweaking the earlier tailored hydrogen bonds. This process may also maintain the elasticity of the related synapses involved in memory storage, a characteristic needed for such networks to alter intricacy and revise endlessly. The primary purpose of this review is to stimulate the efforts to elaborate the mechanism of neuronal connectivity both at molecular and chemical levels.
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http://dx.doi.org/10.1177/1073858414547934DOI Listing
February 2016

A randomized controlled longitudinal naturalistic trial testing the effects of automatic self transcending meditation on heart rate variability in late life depression: study protocol.

BMC Complement Altern Med 2014 Aug 19;14:307. Epub 2014 Aug 19.

Division of Geriatric Psychiatry, Department of Psychiatry, Western University, London N6A 5 W9, ON, Canada.

Background: The prevalence and socioeconomic cost of late life depression (LLD) is on the rise, while the response rate to antidepressant trials remains poor. Various mind-body therapies are being embraced by patients as they are considered safe and potentially effective, yet little is known regarding the effectiveness of such therapies to improve LLD symptoms. Among the mind-body therapies currently in practice, the results of our pilot study have shown that a particular meditation technique called Sahaj Samadhi Meditation, which belongs to the category of meditation termed automatic self-transcending meditation (ASTM) may have some promise in improving cardiovascular autonomic disturbances associated with LLD as well as ameliorating symptoms of depression and anxiety.

Methods/design: Patients between the ages of 60 and 85 with LLD will be randomized either to ASTM plus treatment as usual (TAU) or TAU alone to assess changes in cardiovascular autonomic parameters, neuropsychological symptoms of depression and anxiety as well as quality of life. The instructional phase of the intervention consists of 4 consecutive days of meditation training, after which participants are encouraged to meditate twice daily for twenty minutes each time at home. The intervention also includes once weekly follow up sessions for the subsequent 11 weeks. The planned study has one and a half year recruitment period. Participants will be assessed at baseline and at 4, 8, 12 and 24 weeks post intervention.

Discussion: This study should provide a unique data source from a randomized, controlled, longitudinal trial to investigate the effects of a form of ASTM on cardiovascular autonomic and neuropsychological health in LLD.

Trial Registration: Clinicaltrials.gov NCT02149810, date registered: 05/28/2014.
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http://dx.doi.org/10.1186/1472-6882-14-307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147184PMC
August 2014

Hemodynamic effects of combined focal cerebral ischemia and amyloid protein toxicity in a rat model: a functional CT study.

PLoS One 2014 27;9(6):e100575. Epub 2014 Jun 27.

Imaging Laboratories, Robarts Research Institute, Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada; Imaging Division, Lawson Health Research Institute, London, Ontario, Canada.

Background/objective: Clinical evidence indicates that cerebral ischemia (CI) and a pathological factor of Alzheimer's disease, the β-amyloid (Aβ) protein, can increase the rate of cognitive impairment in the ageing population. Using the CT Perfusion (CTP) functional imaging, we sought to investigate the interaction between CI and the Aβ protein on cerebral hemodynamics.

Methods: A previously established rat model of CI and Aβ was used for the CTP study. Iodinated contrast was given intravenously, while serial CT images of sixteen axial slices were acquired. Cerebral blood flow (CBF) and blood volume (CBV) parametric maps were co-registered to a rat brain atlas and regions of interest were drawn on the maps. Microvascular alteration was investigated with histopathology.

Results: CTP results revealed that ipsilateral striatum of Aβ+CI and CI groups showed significantly lower CBF and CBV than control at the acute phase. Striatal CBF and CBV increased significantly at week 1 in the CI and Aβ+CI groups, but not in the Aβ alone or control group. Histopathology showed that average density of dilated microvessels in the ipsilateral striatum in CI and Aβ+CI groups was significantly higher than control at week 1, indicating this could be associated with hyperperfusion and hypervolemia observed from CTP results.

Conclusion: These results demonstrate that CTP can quantitatively measure the hemodynamic disturbance on CBF and CBV functional maps in a rat model of CI interacting with Aβ.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0100575PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074060PMC
October 2015

Protein markers of cerebrovascular disruption of neurovascular unit: immunohistochemical and imaging approaches.

Rev Neurosci 2014 ;25(4):481-507

Currently, there is great interest in the assembly and function of cerebral endothelial, glial and neuronal cells that form the anatomical basis of the neurovascular unit (NVU) to maintain blood-brain barrier (BBB) and cerebral blood flow. Recent studies have provided considerable insight into the assembly of the components of the NVU. However, there is still paucity of data regarding the identification and expression pattern of these components in various pathologies of the central nervous system. Here, we provide a brief overview of the histological and imaging methods to study BBB disruption in various experimental settings especially the ischemia models associated with necrosis. Emphasis is on the immunohistochemistry of various protein markers of NVU. An understanding of the alterations in the expression pattern of these markers in various neurodegenerative disorders could lead to a better understanding of the conditions that cause BBB disruption as well as to the development of new restorative and protective treatments.
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http://dx.doi.org/10.1515/revneuro-2013-0041DOI Listing
May 2015

Comorbid rat model of ischemia and β-amyloid toxicity: striatal and cortical degeneration.

Brain Pathol 2015 Jan 19;25(1):24-32. Epub 2014 May 19.

CIHR Group on Vascular Cognitive Impairment, Department of Anatomy and Cell Biology, Western University, London, ON, Canada.

Levels of cerebral amyloid, presumably β-amyloid (Abeta), toxicity and the incidence of cortical and subcortical ischemia increases with age. However, little is known about the severe pathological condition and dementia that occur as a result of the comorbid occurrence of this vascular risk factor and Abeta toxicity. Clinical studies have indicated that small ischemic lesions in the striatum are particularly important in generating dementia in combination with minor amyloid lesions. These cognitive deficits are highly likely to be caused by changes in the cortex. In this study, we examined the viability and morphological changes in microglial and neuronal cells, gap junction proteins (connexin43) and neuritic/axonal retraction (Fer Kinase) in the striatum and cerebral cortex using a comorbid rat model of striatal injections of endothelin-1 (ET1) and Abeta toxicity. The results demonstrated ventricular enlargement, striatal atrophy, substantial increases in β-amyloid, ramified microglia and increases in neuritic retraction in the combined models of stroke and Abeta toxicity. Changes in connexin43 occurred equally in both groups of Abeta-treated rats, with and without focal ischemia. Although previous behavioral tests demonstrated impairment in memory and learning, the visual discrimination radial maze task did not show significant difference, suggesting the cognitive impairment in these models is not related to damage to the dorsolateral striatum. These results suggest an insight into the relationship between cortical/striatal atrophy, pathology and functional impairment.
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http://dx.doi.org/10.1111/bpa.12149DOI Listing
January 2015

Comorbid Aβ toxicity and stroke: hippocampal atrophy, pathology, and cognitive deficit.

Neurobiol Aging 2014 Jul 8;35(7):1605-14. Epub 2014 Jan 8.

Department of Anatomy and Cell Biology, Canadian Institutes of Health Research Group on Vascular Cognitive Impairment, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.

Numerous clinical and epidemiological reports indicate that patients with history of vascular illness such as stroke are more likely to develop dementia as the clinical manifestation of Alzheimer's disease. However, there are little data regarding the pathologic mechanisms that link vascular risk factors to the factors associated with dementia onset. We provide evidence that suggests intriguing detrimental interactions between stroke and β-amyloid (Aβ) toxicity in the hippocampus. Stroke was induced by unilateral striatal injection of endothelin-1, the potent vasoconstrictor. Aβ toxicity was modeled by bilateral intracerebroventricular injections of the toxic fragment Aβ. Gross morphologic changes in comorbid Aβ and stroke rats were enlargement of the lateral ventricles with concomitant shrinkage of the hippocampus. The hippocampus displayed a series of synergistic biochemical alterations, including microgliosis, deposition of Aβ precursor protein fragments, and cellular degeneration. In addition, there was bilateral induction of connexin43, reduced neuronal survival, and impaired dendritic development of adult-born immature neurons in the dentate gyrus of these rats compared with either rats alone. Behaviorally, there was impairment in the hippocampal-based discriminative fear-conditioning to context task indicating learning and memory deficit. These results suggest an insight into the relationship between hippocampal atrophy, pathology, and functional impairment. Our work not only highlights the exacerbated pathology that emerges when Aβ toxicity and stroke occur comorbidly but also demonstrates that this comorbid rat model exhibits physiopathology that is highly characteristic of the human condition.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.01.005DOI Listing
July 2014

Dietary lipids and Alzheimer's disease.

Curr Alzheimer Res 2013 Jun;10(5):542-8

Department of Anatomy & Cell Biology, Western University, London, ON, Canada N6A 5C1.

There is a clear need of dietary recommendations or guidelines at both population and/or individual levels, to prevent the Alzheimer's disease or reduce its symptoms. Though data from cellular and animal models of Alzheimer's disease indicate that dietary lipids ameliorate cognitive deficits or neuropathology associated with this disease. However, the data from the present dietary studies are not standardized. Most dietary research in Alzheimer's disease has not examined and compared the differential effects of each fatty acid with other dietary nutrients. Nutrients, particularly different types of fatty acids, absorb, metabolize, and interact with other lipid or nutrients differently in animals and humans with compromised neurological status. Studies in animals and tissue culture should consider such limitations to predict a better response in patients with Alzheimer's disease. The present commentary emphasizes the significance of examining composite lipids/nutrients rather than single fatty acid or nutrient. This report also provides a brief overview of the key factors need to be considered while planning in-vitro, in-vivo or clinical experiments on the effects of dietary fatty acids on Alzheimer's disease. It is to hope that keeping these considerations in mind more judicious use of dietary regimens will speed up the progress of dietary research into the prevention of Alzheimer's disease.
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http://dx.doi.org/10.2174/1567205011310050010DOI Listing
June 2013

Detrimental effects of arachidonic acid and its metabolites in cellular and mouse models of Alzheimer's disease: structural insight.

Neurobiol Aging 2012 Apr 13;33(4):831.e21-31. Epub 2011 Sep 13.

Zentrum für Molekulare Biologie Heidelberg (ZMBH) University of Heidelberg, Heidelberg, Germany.

Inflammation is believed to be integral to the pathogenesis of Alzheimer's disease (AD). Arachidonic acid (AA) is the most important omega-6 fatty acid and a mediator of inflammatory pathways. High-sensitivity enzyme linked immunosorbent assay shows that AA and its various metabolites; prostaglandins, thromboxanes, and leukotriene B4 resulted in significantly higher secretion of both Abeta40 and 42 peptides. A combination of identical number of alternate cis and trans double bonds either at positions Δ5 or 7Z,13 or 15E (such as PGE(2), PGF(2α), THXB2 and PGF(2α)EA) or at positions Δ6Z,8E,10E,14Z (such as LB4) built in the 3-dimensional structure of 20-carbon fatty acyl chains believed to be responsible for their detrimental action. CP 24,879 and sesamin, 2 inhibitors of the AA pathway suppressed the production of amyloid-beta (Aβ) peptides. Immunoblotting experiments and use of SP-C99 transfected COS-7 cells suggested that AA and its metabolites-driven altered production of Aβ is mediated through gamma-secretase cleavage of amyloid precursor protein (APP). An early-onset AD transgenic mouse model expressing the double-mutant form of human amyloid precursor protein, Swedish (K670N/M671L) and Indiana (V717F), corroborated our in vitro findings by showing higher levels of Abeta and amyloid plaques in the brains, when they were fed chow supplemented with 2% AA. Our work not only supports that AA and its metabolites are involved in the production of Aβ and in the pathogenesis of AD but also contributes to clarify aspects of structure-activity relationship helpful for future nonsteroidal anti-inflammatory drugs (NSAIDs) research.
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http://dx.doi.org/10.1016/j.neurobiolaging.2011.07.014DOI Listing
April 2012

DHA supplemented in peptamen diet offers no advantage in pathways to amyloidosis: is it time to evaluate composite lipid diet?

PLoS One 2011 8;6(9):e24094. Epub 2011 Sep 8.

Department of Biochemistry, University of Western Ontario, London, Ontario, Canada.

Numerous reports have documented the beneficial effects of dietary docosahexaenoic acid (DHA) on beta-amyloid production and Alzheimer's disease (AD). However, none of these studies have examined and compared DHA, in combination with other dietary nutrients, for its effects on plaque pathogenesis. Potential interactions of DHA with other dietary nutrients and fatty acids are conventionally ignored. Here we investigated DHA with two dietary regimes; peptamen (pep+DHA) and low fat diet (low fat+DHA). Peptamen base liquid diet is a standard sole-source nutrition for patients with gastrointestinal dysfunction. Here we demonstrate that a robust AD transgenic mouse model shows an increased tendency to produce beta-amyloid peptides and amyloid plaques when fed a pep+DHA diet. The increase in beta-amyloid peptides was due to an elevated trend in the levels of beta-secretase amyloid precursor protein (APP) cleaving enzyme (BACE), the proteolytic C-terminal fragment beta of APP and reduced levels of insulin degrading enzyme that endoproteolyse beta-amyloid. On the contrary, TgCRND8 mice on low fat+DHA diet (based on an approximately 18% reduction of fat intake) ameliorate the production of abeta peptides and consequently amyloid plaques. Our work not only demonstrates that DHA when taken with peptamen may have a tendency to confer a detrimental affect on the amyloid plaque build up but also reinforces the importance of studying composite lipids or nutrients rather than single lipids or nutrients for their effects on pathways important to plaque development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024094PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169579PMC
March 2012

Additive effects of fatty acid mixtures on the levels and ratio of amyloid β40/42 peptides differ from the effects of individual fatty acids.

J Neurosci Res 2011 Nov 11;89(11):1795-801. Epub 2011 Jul 11.

Zentrum für Molekulare Biologie Heidelberg, University of Heidelberg, Heidelberg, Germany.

Several studies have shown the protective and/or deleterious effects of dietary enrichment of single fatty acids (FAs) in several animal and cell-culture models of Alzheimer's disease (AD). However, potential interactions among dietary fatty acids are traditionally ignored. None of these studies has examined and compared the differential effects of FAs in combination, as well as alone, for their effects on amyloid β production or AD. Here we investigated the effects of omega-9 (oleic acid) and omega-6 (linoleic and arachidonic acids) fatty acids, either alone or combined, on Aβ production by APP-695 and SP-C99 transfected COS-7 cells. Overall, our results are the first to demonstrate that mixtures of FAs alter the production of Aβ40 and Aβ42 peptides and consequently the Aβ40:42 ratio differently from individual FAs. Here we show that the effects of a single lipid on Aβ production are not attributed to that single FA alone. Rather, the overall lipid composition influences the specificity and level of the regulated intramembranous proteolysis of APP by the γ-secretase complex. Our results reinforce the importance of studying composite lipids/nutrients rather than single lipids or nutrients.
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http://dx.doi.org/10.1002/jnr.22706DOI Listing
November 2011

Oleic acid ameliorates amyloidosis in cellular and mouse models of Alzheimer's disease.

Brain Pathol 2011 May 11;21(3):321-9. Epub 2010 Nov 11.

Department of Biochemistry, University of Western Ontario, London, ON, Canada.

Several lines of evidence support protective as well as deleterious effects of oleic acid (OA) on Alzheimer's disease (AD) and other neurological disorders; however, the bases of these effects are unclear. Our investigation demonstrates that amyloid precursor protein (APP) 695 transfected Cos-7 cells supplemented with OA have reduced secreted amyloid-beta (Aβ) levels. An early-onset AD transgenic mouse model expressing the double-mutant form of human APP, Swedish (K670N/M671L) and Indiana (V717F), corroborated our in vitro findings when they were fed a high-protein, low-fat (18% reduction), cholesterol-free diet enriched with OA. These mice exhibited an increase in Aβ40/Aβ42 ratio, reduced levels of beta-site APP cleaving enzyme (BACE) and reduced presenilin levels along with reduced amyloid plaques in the brain. The decrease in BACE levels was accompanied by increased levels of a non-amyloidogenic soluble form of APP (sAPPα). Furthermore, the low-fat/+OA diet resulted in an augmentation of insulin-degrading enzyme and insulin-like growth factor-II. These results suggest that OA supplementation and cholesterol intake restriction in a mouse model of AD reduce AD-type neuropathology.
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http://dx.doi.org/10.1111/j.1750-3639.2010.00449.xDOI Listing
May 2011

Structural insight into the differential effects of omega-3 and omega-6 fatty acids on the production of Abeta peptides and amyloid plaques.

J Biol Chem 2011 Feb 22;286(8):6100-7. Epub 2010 Oct 22.

Zentrum für Molekulare Biologie Heidelberg, University of Heidelberg, Heidelberg, Germany.

Several studies have shown the protective effects of dietary enrichment of various lipids in several late-onset animal models of Alzheimer Disease (AD); however, none of the studies has determined which structure within a lipid determines its detrimental or beneficial effects on AD. High-sensitivity enzyme-linked immunosorbent assay (ELISA) shows that saturated fatty acids (SFAs), upstream omega-3 FAs, and arachidonic acid (AA) resulted in significantly higher secretion of both Aβ 40 and 42 peptides compared with long chain downstream omega-3 and monounsaturated FAs (MUFA). Their distinct detrimental action is believed to be due to a structural template found in their fatty acyl chains that lack SFAs, upstream omega-3 FAs, and AA. Immunoblotting experiments and use of APP-C99-transfected COS-7 cells suggest that FA-driven altered production of Aβ is mediated through γ-secretase cleavage of APP. An early-onset AD transgenic mouse model expressing the double-mutant form of human amyloid precursor protein (APP); Swedish (K670N/M671L) and Indiana (V717F), corroborated in vitro findings by showing lower levels of Aβ and amyloid plaques in the brain, when they were fed a low fat diet enriched in DHA. Our work contributes to the clarification of aspects of structure-activity relationships.
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http://dx.doi.org/10.1074/jbc.M110.183608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057860PMC
February 2011

Phospholipids and a phospholipid-rich diet alter the in vitro amyloid-beta peptide levels and amyloid-beta 42/40 ratios.

Neurosci Lett 2010 Sep 19;481(2):73-7. Epub 2010 Jun 19.

Zentrum für Molekulare Biologie Heidelberg, University of Heidelberg, Germany.

Amyloid-beta peptides (Abeta) generated by proteolysis of the beta-amyloid precursor protein (APP) by beta- and gamma-secretases play an important role in the pathogenesis of Alzheimer's disease (AD). There is mounting evidence that the lipid matrix of neuronal cell membranes plays an important role in the accumulation of Abeta peptides into senile plaques, one of the hallmarks of AD. With the aim to clarify the molecular basis of the interaction between Abeta and cellular membranes, we investigated the effects of various phospholipids (PLs) and a PL-rich diet on Abeta production. Here we show that modulation of Abeta production and Abeta42:40 ratio is not limited to individual fatty acids, rather it is the composition of the PLs of the membrane bilayer, that influences the specificity and level of the regulated intramembranous proteolysis of APP by the gamma-secretase complex. We show that Abeta levels in the conditioned media, in response to some of the PL supplements, is increased in the center and decreased on either side of a graph that resembles bell-shaped distribution. This means that the PLs have less of a tendency to produce unusually extreme effects on Abeta production in SP-C99 transfected Cos-7 cultured cells. We proposed a mechanism-based hypothesis to rationalize PLs' effects on Abeta production.
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http://dx.doi.org/10.1016/j.neulet.2010.06.046DOI Listing
September 2010