Khaled S. Abd-Elrahman
@ucalgary.ca
Smooth Muscle Research Group, Cumming School of Medicine
University of Calgary in Alberta
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
Sara Aljoudi, Hamdan Hamdan, and Khaled S. Abd-Elrahman
Medknow
Khaled S. Abd-Elrahman, Tash-Lynn L. Colson, Shaarika Sarasija, and Stephen S.G. Ferguson
Elsevier BV
Khaled S. Abd-Elrahman, Jean-Martin Beaulieu, and Stephen S. G. Ferguson
Frontiers Media SA
Nadia Rabeh, Baraa Hajjar, Jude O. Maraka, Ashwin F. Sammanasunathan, Mohammed Khan, Saif M.I. Alkhaaldi, Samy Mansour, Rashed T. Almheiri, Hamdan Hamdan, and Khaled S. Abd-Elrahman
Elsevier BV
Si Han Li, Tash-Lynn L. Colson, Jingwei Chen, Khaled S. Abd-Elrahman, and Stephen S. G. Ferguson
Springer Science and Business Media LLC
AbstractHuntington’s Disease (HD) is an inherited autosomal dominant neurodegenerative disorder that leads to progressive motor and cognitive impairment due to the expansion of a polyglutamine (CAG) repeat in the N-terminal region of the huntingtin (Htt) protein. The creation of HD mouse models represents a critical step in the research for HD treatment. Among the currently available HD mouse models, the zQ175 knock-in mouse line is the first to display robust disease phenotype on a heterozygous background. The newer FDNQ175 mouse model is derived from the zQ175 mouse line and presents a more aggressive phenotype. Moreover, increasing evidence has implicated sex as a contributing factor in the progression of HD symptoms. Here, we compared the progression of HD phenotypes in male and female heterozygous FDNQ175 mice. We found that both male and female heterozygous mice showed deficits in forelimb grip strength and cognition as early as 6 months of age. However, female FDNQ175 mice were less vulnerable to HD-associated decline in limb coordination and movement. Neither male nor female FDNQ175 mice exhibited reduced locomotor activity in the open field or exhibit consistent differences in anxiety at 6–12 months of age. Both male and female FDNQ175 mice exhibited increased numbers of huntingtin aggregates with age and 8-month-old female FDNQ175 mice had significantly more aggregates than their male counterparts. Taken together, our results provide further evidence that sex can influence the progression of HD phenotype in preclinical animal models and must be taken into consideration for future HD research.
Karim S. Ibrahim, Salah El Mestikawy, Khaled S. Abd-Elrahman, and Stephen S.G. Ferguson
Society for Neuroscience
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disease characterized by progressive motor and cognitive impairments, with no disease-modifying therapies yet available. HD pathophysiology involves evident impairment in glutamatergic neurotransmission leading to severe striatal neurodegeneration. The vesicular glutamate transporter-3 (VGLUT3) regulates the striatal network that is centrally affected by HD. Nevertheless, current evidence on the role of VGLUT3 in HD pathophysiology is lacking. Here, we crossed mice lackingSlc17a8gene (VGLUT3–/–) with heterozygouszQ175knock-in mouse model of HD (zQ175:VGLUT3–/–). Longitudinal assessment of motor and cognitive functions from 6 to 15 months of age reveals that VGLUT3 deletion rescues motor coordination and short-term memory deficits in both male and femalezQ175mice. VGLUT3 deletion also rescues neuronal loss likely via the activation of Akt and ERK1/2 in the striatum ofzQ175mice of both sexes. Interestingly, the rescue in neuronal survival inzQ175:VGLUT3–/–mice is accompanied by a reduction in the number of nuclear mutant huntingtin (mHTT) aggregates with no change in the total aggregate levels or microgliosis. Collectively, these findings provide novel evidence that VGLUT3, despite its limited expression, can be a vital contributor to HD pathophysiology and a viable target for HD therapeutics.SIGNIFICANCE STATEMENTDysregulation of the striatal network centrally contributes to the pathophysiology of Huntington's disease (HD). The atypical vesicular glutamate transporter-3 (VGLUT3) has been shown to regulate several major striatal pathologies, such as addiction, eating disorders, or L-DOPA-induced dyskinesia. Yet, our understanding of VGLUT3's role in HD remains unclear. We report here that deletion of theSlc17a8(Vglut3) gene rescues the deficits in both motor and cognitive functions in HD mice of both sexes. We also find that VGLUT3 deletion activates neuronal survival signaling and reduces nuclear aggregation of abnormal huntingtin proteins and striatal neuron loss in HD mice. Our novel findings highlight the vital contribution of VGLUT3 in HD pathophysiology that can be exploited for HD therapeutic management.
Khaled S. Abd-Elrahman, Stephen S.G. Ferguson, and Shaarika Sarasija
Bentham Science Publishers Ltd.
: Glutamate, the major excitatory neurotransmitter in the brain exerts its effects via both ionotropic glutamate receptors and metabotropic glutamate receptors (mGluRs). There are three subgroups of mGluRs, pre-synaptic Group II and Group III mGluRs and post-synaptic Group I mGluRs. mGluRs are ubiquitously expressed in the brain and their activation is poised upstream of a myriad of signaling pathways, resulting in their implication in the pathogenesis of various neurodegenerative diseases including, Alzheimer’s Disease (AD). While the exact mechanism of AD etiology remains elusive, β-amyloid (Aβ) plaques and hyperphosphorylated tau tangles remain the histopathological hallmarks of AD. Though less electrically excitable, neuroglia are a major non-neuronal cell type in the brain and are composed of astrocytes, microglia, and oligodendrocytes. Astrocytes, microglia, and oligodendrocytes provide structural and metabolic support, active immune defence, and axonal support and sheathing, respectively. Interestingly, Aβ and hyperphosphorylated tau are known to disrupt the neuroglial homeostasis in the brain, pushing them towards a more neurotoxic state. In this review, we discuss what is currently known regarding the expression patterns of various mGluRs in neuroglia and how Aβ and tau alter the normal mGluR function in the neuroglia and contribute to the pathophysiology of AD.
Ibrahim AlZaim, Ali H. Eid, Khaled S. Abd-Elrahman, and Ahmed F. El-Yazbi
Elsevier BV
Si Han Li, Khaled S. Abd-Elrahman, and Stephen S.G. Ferguson
Elsevier BV
Ahmed F. El-Yazbi, Ali H. Eid, Fouad A. Zouein, and Khaled S. Abd-Elrahman
Frontiers Media SA
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt, Faculty of Pharmacy, Alamein International University, Al Alamein, Egypt, Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar, Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Department of Signaling and Cardiovascular Pathophysiology, UMR-S 1180, Inserm, Université ParisSaclay, Paris-Saclay, France, The Cardiovascular Renal and Metabolic Diseases Research Center of Excellence, American University of Beirut Medical Center, Beirut, Lebanon, Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center, Jackson, MS, United States, Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada, Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates
Karim S. Ibrahim, Salah El Mestikawy, Khaled S. Abd-Elrahman, and Stephen S.G. Ferguson
Society for Neuroscience
Abstract Type 3 vesicular glutamate transporter (VGLUT3) represents a unique modulator of glutamate release from both nonglutamatergic and glutamatergic varicosities within the brain. Despite its limited abundance, VGLUT3 is vital for the regulation of glutamate signaling and, therefore, modulates the activity of various brain microcircuits. However, little is known about how glutamate receptors are regulated by VGLUT3 across different brain regions. Here, we used VGLUT3 constitutive knock-out (VGLUT3–/–) mice and explored how VGLUT3 deletion influences total and cell surface expression of different ionotropic and metabotropic glutamate receptors. VGLUT3 deletion upregulated the overall expression of metabotropic glutamate receptors mGluR5 and mGluR2/3 in the cerebral cortex. In contrast, no change in the total expression of ionotropic NMDAR glutamate receptors were observed in the cerebral cortex of VGLUT3–/– mice. We noted significant reduction in cell surface levels of mGluR5, NMDAR2A, NMDAR2B, as well as reductions in dopaminergic D1 receptors and muscarinic M1 acetylcholine receptors in the hippocampus of VGLUT3–/– mice. Furthermore, mGluR2/3 total expression and mGluR5 cell surface levels were elevated in the striatum of VGLUT3–/– mice. Last, AMPAR subunit GluA1 was significantly upregulated throughout cortical, hippocampal, and striatal brain regions of VGLUT3–/– mice. Together, these findings complement and further support the evidence that VGLUT3 dynamically regulates glutamate receptor densities in several brain regions. These results suggest that VGLUT3 may play an intricate role in shaping glutamatergic signaling and plasticity in several brain areas.
Walaa Fakih, Ralph Zeitoun, Ibrahim AlZaim, Ali H. Eid, Firas Kobeissy, Khaled S. Abd‐Elrahman, and Ahmed F. El‐Yazbi
Wiley
The metabolic syndrome comprises a family of clinical and laboratory findings, including insulin resistance, hyperglycemia, hypertriglyceridemia, low high‐density lipoprotein cholesterol levels, and hypertension, in addition to central obesity. The syndrome confers a high risk of cardiovascular mortality. Indeed, metabolic dysfunction has been shown to cause a direct insult to smooth muscle and endothelial components of the vasculature, which leads to vascular dysfunction and hyperreactivity. This, in turn, causes cerebral vasoconstriction and hypoperfusion, eventually contributing to cognitive deficits. Moreover, the metabolic syndrome disrupts key homeostatic processes in the brain, including apoptosis, autophagy, and neurogenesis. Impairment of such processes in the context of metabolic dysfunction has been implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer, Parkinson, and Huntington diseases.
Khaled S. Abd‐Elrahman, Shaarika Sarasija, Tash‐Lynn L. Colson, and Stephen S. G. Ferguson
Wiley
BACKGROUND AND PURPOSE
Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline and women account for 60% of diagnosed cases. Beta-amyloid (Aβ) oligomers is considered the principal neurotoxic species in AD brains. The M1 muscarinic acetylcholine receptor (M1 mAChR) plays a key role in memory and learning. M1 mAChR agonists show pro-cognitive activity but cause many adverse off-target effects. A new orally bioavailable M1 mAChR positive allosteric modulator (PAM), VU0486846, is devoid of direct agonist activity or adverse effects but was not tested for disease-modifying efficacy in female AD mice.
EXPERIMENTAL APPROACH
Nine-month-old female APPswe/PSEN1ΔE9 (APPswe) and wildtype mice were treated with VU0486846 in drinking water (10mg/kg/day) for 4 or 8 weeks. Cognitive function of mice was assessed after treatment and brains were harvested for biochemical and immunohistochemical assessment.
KEY RESULTS
VU0486846 improved cognitive function of APPswe mice when tested in novel object recognition and Morris water maze. This was paralleled by a significant reduction in Aβ oligomers and plaques and neuronal loss in hippocampus. VU0486846 reduced Aβ oligomer production in APPswe mice by increasing M1 mAChR expression and shifting the processing of amyloid precursor protein from amyloidogenic cleavage to non-amyloidogenic cleavage. Specifically, VU0486846 reduced the expression of β-secretase 1 (BACE1), whereas it enhanced the expression of the α-secretase ADAM10 in APPswe hippocampus.
CONCLUSION AND IMPLICATIONS
Using M1 mAChR PAMs can be a viable disease-modifying approach that should be exploited clinically to slow AD in women.
Si Han Li, Tash-Lynn L. Colson, Khaled S. Abd-Elrahman, and Stephen S. G. Ferguson
Frontiers Media SA
Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disorder that leads to progressive motor and cognitive impairment. There are currently no available disease modifying treatments for HD patients. We have previously shown that pharmacological blockade of metabotropic glutamate receptor 5 (mGluR5) signaling rescues motor deficits, improves cognitive impairments and mitigates HD neuropathology in male zQ175 HD mice. Mounting evidence indicates that sex may influence HD progression and we have recently reported a sex-specific pathological mGluR5 signaling in Alzheimer’s disease (AD) mice. Here, we compared the outcomes of treatment with the mGluR5 negative allosteric modulator CTEP (2-chloro-4-[2-[2,5-dimethyl-1-[4-(trifluoromethoxy)phenyl]imidazol-4-yl]ethynyl]pyridine) in both male and female symptomatic zQ175 mice. We found that female zQ175 mice required a longer treatment duration with CTEP than male mice to show improvement in their rotarod performance. Unlike males, chronic CTEP treatment did not improve the grip strength nor reverse the cognitive decline of female zQ175 mice. However, CTEP reduced the number of huntingtin aggregates, improved neuronal survival and decreased microglia activation in the striatum of both male and female zQ175 mice. Together, our results indicate that mGluR5 antagonism can reduce HD neuropathology in both male and female zQ175 HD mice, but sex has a clear impact on the efficacy of the treatment and must be taken into consideration for future HD drug development.
Khaled S. Abd-Elrahman and Stephen S.G. Ferguson
Annual Reviews
Metabotropic glutamate receptor 5 (mGluR5) is ubiquitously expressed in brain regions responsible for memory and learning. It plays a key role in modulating rapid changes in synaptic transmission and plasticity. mGluR5 supports long-term changes in synaptic strength by regulating the transcription and translation of essential synaptic proteins. β-Amyloid 42 (Aβ42) oligomers interact with a mGluR5/cellular prion protein (PrPC) complex to disrupt physiological mGluR5 signal transduction. Aberrant mGluR5 signaling and associated synaptic failure are considered an emerging pathophysiological mechanism of Alzheimer's disease (AD). Therefore, mGluR5 represents an attractive therapeutic target for AD, and recent studies continue to validate the efficacy of various mGluR5 allosteric modulators in improving memory deficits and mitigating disease pathology. However, sex-specific differences in the pharmacology of mGluR5 and activation of noncanonical signaling downstream of the receptor suggest that its utility as a therapeutic target in female AD patients needs to be reconsidered.
Si Han Li, Tash-Lynn L. Colson, Khaled S. Abd-Elrahman, and Stephen S.G. Ferguson
American Society for Pharmacology & Experimental Therapeutics (ASPET)
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease that leads to progressive motor impairments with no available disease-modifying treatment. Current evidence indicates that exacerbated postsynaptic glutamate signaling in the striatum plays a key role in the pathophysiology of HD. However, it remains unclear whether reducing glutamate release can be an effective approach to slow the progression of HD. Here, we show that the activation of metabotropic glutamate receptors 2 and 3 (mGluR2/3), which inhibit presynaptic glutamate release, improves HD symptoms and pathology in heterozygous zQ175 knockin mice. Treatment of both male and female zQ175 mice with the potent and selective mGluR2/3 agonist LY379268 for either 4 or 8 weeks improves both limb coordination and locomotor function in all mice. LY379268 also reduces mutant huntingtin aggregate formation, neuronal cell death, and microglial activation in the striatum of both male and female zQ175 mice. The reduction in mutant huntingtin aggregates correlates with the activation of a glycogen synthase kinase 3β–dependent autophagy pathway in male, but not female, zQ175 mice. Furthermore, LY379268 reduces both Akt and ERK1/2 phosphorylation in male zQ175 mice but increases both Akt and ERK1/2 phosphorylation in female zQ175 mice. Taken together, our results indicate that mGluR2/3 activation mitigates HD neuropathology in both male and female mice but is associated with the differential activation and inactivation of cell signaling pathways in heterozygous male and female zQ175 mice. This further highlights the need to take sex into consideration when developing future HD therapeutics. SIGNIFICANCE STATEMENT The mGluR2/3 agonist LY379268 improves motor impairments and reduces pathology in male and female zQ175 Huntington’s disease mice. The beneficial outcomes of LY379268 treatment in Huntington’s disease mice were mediated by divergent cell signaling pathways in both sexes. We provide evidence that mGluR2/3 agonists can be repurposed for the treatment of Huntington’s disease, and we emphasize the importance of investigating sex as a biological variable in preclinical disease-modifying studies.
Karim S. Ibrahim, Caitlyn J. McLaren, Khaled S. Abd-Elrahman, and Stephen S.G. Ferguson
Elsevier BV
Optineurin (OPTN) is a multifunctional protein that mediates a network of cellular processes regulating membrane trafficking, inflammatory responses and autophagy. The OPTN-rich interactome includes Group I metabotropic glutamate receptors (mGluR1 and 5), members of the Gαq/11 protein receptor family. Recent evidence has shown that mGluR5, in addition to its canonical Gαq/11 protein-coupled signaling, regulates autophagic machinery via mTOR/ULK1 and GSK3β/ZBTB16 pathways in both Alzheimer's and Huntington's disease mouse models. Despite its potential involvement, the role of OPTN in mediating mGluR5 downstream signaling cascades remains largely unknown. Here, we employed a CRISPR/Cas9 OPTN-deficient STHdhQ7/Q7 striatal cell line and global OPTN knockout mice to investigate whether Optn gene deletion alters both mGluR5 canonical and noncanonical signaling. We find that OPTN is required for mGluR5-activated Ca2+ flux and ERK1/2 signaling following receptor activation in STHdhQ7/Q7 cells and acute hippocampal slices. Deletion of OPTN impairs both GSK3β/ZBTB16 and mTOR/ULK1 autophagic signaling in STHdhQ7/Q7 cells. Furthermore, mGluR5-dependent regulation of GSK3β/ZBTB16 and mTOR/ULK-1 autophagic signaling is impaired in hippocampal slices of OPTN knockout mice. Overall, we show that the crosstalk between OPTN and mGluR5 can have major implication on receptor signaling and therefore potentially contribute to the pathophysiology of neurodegenerative diseases.
Khaled Abdelrahman and Raafat El-Hacha
Canadian Science Publishing
The critical need to enhance existing strengthening methods with more efficient and effective ones has led to the evolvement of smarter and innovative class of materials termed shape memory alloys (SMA). The SMAs possess unique characteristic properties that lie in their ability to undergo large deformations and return to their undeformed shape through stress removal or heating process. Limited research studies conducted using SMAs have shown high potential for their use in building industry. Results presented in this research study are from an experimental study that investigated the compressive behaviour of uniaxial concentrically loaded nickel–titanium (Ni–Ti) SMA-spirally confined RC columns and compared with RC columns confined with conventional carbon fibre reinforced polymer (CFRP) sheets. The compression tests revealed that actively confining the concrete column with Ni–Ti SMA spiral wires increased the performance of the concrete dramatically. Additionally, the active Ni–Ti SMA-confinement system exhibited superior performance compared to the conventional passive CFRP-confinement system.
Rana A. Alaaeddine, Ibrahim AlZaim, Safaa H. Hammoud, Aya Arakji, Ali H. Eid, Khaled S. Abd-Elrahman, and Ahmed F. El-Yazbi
Portland Press Ltd.
Abstract Antithrombotic drugs are widely used for primary and secondary prevention, as well as treatment of many cardiovascular disorders. Over the past few decades, major advances in the pharmacology of these agents have been made with the introduction of new drug classes as novel therapeutic options. Accumulating evidence indicates that the beneficial outcomes of some of these antithrombotic agents are not solely related to their ability to reduce thrombosis. Here, we review the evidence supporting established and potential pleiotropic effects of four novel classes of antithrombotic drugs, adenosine diphosphate (ADP) P2Y12-receptor antagonists, Glycoprotein IIb/IIIa receptor Inhibitors, and Direct Oral Anticoagulants (DOACs), which include Direct Factor Xa (FXa) and Direct Thrombin Inhibitors. Specifically, we discuss the molecular evidence supporting such pleiotropic effects in the context of cardiovascular disease (CVD) including endothelial dysfunction (ED), atherosclerosis, cardiac injury, stroke, and arrhythmia. Importantly, we highlight the role of DOACs in mitigating metabolic dysfunction-associated cardiovascular derangements. We also postulate that DOACs modulate perivascular adipose tissue inflammation and thus, may reverse cardiovascular dysfunction early in the course of the metabolic syndrome. In this regard, we argue that some antithrombotic agents can reverse the neurovascular damage in Alzheimer’s and Parkinson’s brain and following traumatic brain injury (TBI). Overall, we attempt to provide an up-to-date comprehensive review of the less-recognized, beneficial molecular aspects of antithrombotic therapy beyond reduced thrombus formation. We also make a solid argument for the need of further mechanistic analysis of the pleiotropic effects of antithrombotic drugs in the future.
Khaled S. Abd-Elrahman, Awatif Albaker, Jessica M. de Souza, Fabiola M. Ribeiro, Michael G. Schlossmacher, Mario Tiberi, Alison Hamilton, and Stephen S. G. Ferguson
American Association for the Advancement of Science (AAAS)
A sex-specific prion-amyloid interaction predicts that some Alzheimer’s disease therapies may not work in female patients. Men only for an Alzheimer’s drug target β-Amyloid (Aβ) deposits in the brain contribute to the progression of Alzheimer’s disease (AD) by inducing excitotoxic signaling in neurons. Aβ binds to the metabotropic glutamate receptor mGluR5, and pharmacological inhibition of mGluR5 reverses cognitive decline in male AD model animals. However, Abd-Elrahman et al. found that Aβ bound to mGluR5 in postmortem brain tissue only from male AD model mice and male human donors. This sex-selective interaction was mediated by prion protein in male mouse brain tissue. The findings suggest that mGluR5 inhibitors may be therapeutically beneficial only for male patients with AD. The prevalence, presentation, and progression of Alzheimer’s disease (AD) differ between men and women, although β-amyloid (Aβ) deposition is a pathological hallmark of AD in both sexes. Aβ-induced activation of the neuronal glutamate receptor mGluR5 is linked to AD progression. However, we found that mGluR5 exhibits distinct sex-dependent profiles. Specifically, mGluR5 isolated from male mouse cortical and hippocampal tissues bound with high affinity to Aβ oligomers, whereas mGluR5 from female mice exhibited no such affinity. This sex-selective Aβ-mGluR5 interaction did not appear to depend on estrogen, but rather Aβ interaction with cellular prion protein (PrPC), which was detected only in male mouse brain homogenates. The ternary complex between mGluR5, Aβ oligomers, and PrPC was essential to elicit mGluR5-dependent pathological suppression of autophagy in primary neuronal cultures. Pharmacological inhibition of mGluR5 reactivated autophagy, mitigated Aβ pathology, and reversed cognitive decline in male APPswe/PS1ΔE9 mice, but not in their female counterparts. Aβ oligomers also bound with high affinity to human mGluR5 isolated from postmortem donor male cortical brain tissue, but not that from female samples, suggesting that this mechanism may be relevant to patients. Our findings indicate that mGluR5 does not contribute to Aβ pathology in females, highlighting the complexity of mGluR5 pharmacology and Aβ signaling that supports the need for sex-specific stratification in clinical trials assessing AD therapeutics.
Karim S. Ibrahim, Khaled S. Abd-Elrahman, Salah El Mestikawy, and Stephen SG Ferguson
American Society for Pharmacology & Experimental Therapeutics (ASPET)
Crosstalk between both pre- and post-synaptic components of glutamatergic neurotransmission plays a crucial role in orchestrating a multitude of brain functions including synaptic plasticity and motor planning. Metabotropic glutamate receptor 5 (mGluR5) exhibits a promising therapeutic potential for many neurodevelopmental and neurodegenerative disorders, as the consequence of its modulatory control over diverse neuronal networks required for memory, motor coordination, neuronal survival and differentiation. Given these crucial roles, mGluR5 signaling is under the tight control of glutamate release machinery mediated through vesicular glutamate transporters (VGLUTs) to ultimately dictate glutamatergic output. A particular VGLUT isoform, VGLUT3, exhibits an overlapping, but unique, distribution with mGluR5 and the dynamic crosstalk between mGluR5 and VGLUT3 is key for the function of specific neuronal networks involved in motor coordination, emotions and cognition. Thus, aberrant signaling of the VGLUT3/mGluR5 axis is linked to various pathologies including, but not limited to, Parkinson's disease, anxiety disorders and drug addiction. We argue that a comprehensive profiling of how coordinated VGLUT3/mGluR5 signaling influences overall glutamatergic neurotransmission is warranted. Significance Statement Vesicular glutamate receptor 3 (VGLUT3) machinery orchestrates glutamate release and its distribution overlaps with metabotropic glutamate receptor 5 (mGluR5) in regional brain circuitries including striatum, hippocampus and raphe nucleus. Therefore, VGLUT3/mGluR5 crosstalk can significantly influences both physiological and pathophysiological glutamatergic neurotransmission. Pathological signaling of the VGLUT3/mGluR5 axis is linked to Parkinson's disease, anxiety disorders and drug addiction. However, it is also predicted to contribute to other motor and cognitive disorders.
Jéssica M. de Souza, Khaled S. Abd-Elrahman, Fabiola M. Ribeiro, and Stephen S. G. Ferguson
Springer Science and Business Media LLC
AbstractRepressor element 1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a transcription repressor and its expression is regulated by the Wnt pathway through β-catenin. Metabotropic glutamate receptor 5 (mGluR5) signaling plays a key role in controlling neuronal gene expression. Interestingly, REST/NRSF nuclear translocation and signaling, as well as mGluR5 signaling are altered in the presence of mutant huntingtin. It remains unclear whether mGluR5 can modulate Wnt and REST/NRSF signaling under physiological conditions and whether this modulation is altered in Huntington’s disease (HD). Using primary corticostriatal neurons derived from wild type mouse embryos, we find that targeting mGluR5 using the agonist, DHPG, or the negative allosteric modulator, CTEP, modulates REST/NRSF expression by regulating the assembly of N-cadherin/ β-catenin complex in a Src kinase-dependent manner. We have validated our in vitro findings in vivo using two HD mouse models. Specifically, we show that pharmacological inhibition of mGluR5 in zQ175 mice and genetic ablation of mGluR5 in BACHD mice corrected the pathological activation of Src and rescued REST/NRSF-dependent signaling. Together, our data provide evidence that mGluR5 regulates REST/NRSF expression via the Wnt pathway and highlight the contribution of impaired REST/ NRSF signaling to HD pathology.
Raafat El-Hacha and Khaled Abdelrahman
Elsevier BV
Khaled Abdelrahman and Raafat El-Hacha
Elsevier BV
Khaled S. Abd-Elrahman, Alison Hamilton, Awatif Albaker, and Stephen S. G. Ferguson
American Chemical Society (ACS)
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and is characterized by a progressive cognitive decline in affected individuals. Current therapeutic strategies are limited in their efficacy and some have proven to be even less effective at later disease stages or after extended use. We previously demonstrated that chronic inhibition of mGluR5 signaling using the selective negative allosteric modulator (NAM) CTEP in APPswe/PS1ΔE9 mice can rescue cognitive function, activating the ZBTB16-mediated autophagy pathway to reduce Aβ, the principal neurotoxic species in AD brains. Here, we evaluated the efficacy of long-term treatment with CTEP in 6 month old APPswe/PS1ΔE9 mice for either 24 or 36 weeks. CTEP maintained its efficacy in reversing working and spatial memory deficits and mitigating neurogliosis in APPswe/PS1ΔE9 mice when administered for 24 weeks. This was paralleled by a significant reduction in Aβ oligomer and plaque load as a result of autophagy activation via ZBTB16 and mTOR-dependent pathways. However, further extension of CTEP treatment for 36 weeks was found ineffective in reversing memory deficit, neurogliosis, or Aβ-related pathology. We found that this loss in CTEP efficacy in 15 month old APPswe/PS1ΔE9 mice was due to the abolished contribution of ZBTB16 and mTOR-mediated signaling to AD neuropathology at this advanced disease stage. Our findings indicate that the contribution of pathological mGluR5-signaling to AD may shift as the disease progresses. Thus, we provide the first evidence that the underlying pathophysiological mechanism(s) of AD may unfold along the course of the disease and treatment strategies should be modified accordingly to ensure maximal therapeutic outcomes.