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Differential aberrant structural synaptic plasticity in axons and dendrites ahead of their degeneration in tauopathy [article]

Johanna S Jackson, James D Johnson, Soraya Meftah, Tracey K Murray, Zeshan Ahmed, Matteo Fasiolo, Michael L Hutton, John TR Isaac, Michael J O'Neill, Michael C Ashby
2020 bioRxiv   pre-print
Neurodegeneration driven by aberrant tau is a key feature of many dementias. Pathological stages of tauopathy are characterised by reduced synapse density and altered synapse function. Furthermore, changes in synaptic plasticity have been documented in the early stages of tauopathy suggesting that they may be a driver of later pathology. However, it remains unclear if synapse plasticity is specifically linked to the degeneration of neurons. This is partly because, in progressive dementias,
more » ... logy can vary widely from cell-to-cell along the prolonged disease time-course. To overcome this variability, we have taken a longitudinal experimental approach to track individual neurons through the progression of neurodegenerative tauopathy. Using repeated in vivo 2-photon imaging in rTg4510 transgenic mice, we have measured structural plasticity of presynaptic terminaux boutons and postsynaptic spines on individual axons and dendrites over long periods of time. By following individual neurons, we have measured synapse density across the neuronal population and tracked changes in synapse turnover in each neuron. We found that tauopathy drives a reduction in density of both presynaptic and postsynaptic structures and that this is partially driven by degeneration of individual axons and dendrites that are spread widely across the disease time-course. Both synaptic loss and neuronal degeneration was ameliorated by reduction in expression of the aberrant P301L transgene, but only if that reduction was initiated early in disease progression. Notably, neurite degeneration was preceded by alterations in synapse turnover that contrasted in axons and dendrites. In dendrites destined to die, there was a dramatic loss of spines in the week immediately before degeneration. In contrast, axonal degeneration was preceded by a progressive attenuation of presynaptic turnover that started many weeks before axon disappearance. Therefore, changes in synapse plasticity are harbingers of degeneration of individual neurites that occur at differing stages of tau-driven neurodegenerative disease, suggesting a cell or neurite autonomous process. Furthermore, the links between synapse plasticity and degeneration are distinct in axonal and dendritic compartments.
doi:10.1101/2020.04.29.067629 fatcat:6jv4sawrw5hkxer7lgi6qidppa

Tracking progressive pathological and functional decline in the rTg4510 mouse model of tauopathy

Thomas Blackmore, Soraya Meftah, Tracey Karen Murray, Peter James Craig, Anthony Blockeel, Keith Phillips, Brian Eastwood, Michael J. O'Neill, Hugh Marston, Zeshan Ahmed, Gary Gilmour, Francois Gastambide
2017 Alzheimer's Research & Therapy  
The choice and appropriate use of animal models in drug discovery for Alzheimer's disease (AD) is pivotal to successful clinical translation of novel therapeutics, yet true alignment of research is challenging. Current models do not fully recapitulate the human disease, and even exhibit various degrees of regional pathological burden and diverse functional alterations. Given this, relevant pathological and functional endpoints must be determined on a model-by-model basis. The present work
more » ... es the rTg4510 mouse model of tauopathy as a case study to define best practices for the selection and validation of cognitive and functional endpoints for the purposes of pre-clinical AD drug discovery. Methods: Male rTg4510 mice were first tested at an advanced age, 12 months, in multiple behavioural assays (step 1). Severe tau pathology and neurodegeneration was associated with profound locomotor hyperactivity and spatial memory deficits. Four of these assays were then selected for longitudinal assessment, from 4 to 12 months, to investigate whether behavioural performance changes as a function of accumulation of tau pathology (step 2). Experimental suppression of tau pathology-via doxycycline administration-was also investigated for its effect on functional performance. Results: Progressive behavioural changes were detected where locomotor activity and rewarded alternation were found to most closely correlate with tau burden and neurodegeneration. Doxycycline initiated at 4 months led to a 50% suppression of transgene expression, which was sufficient to prevent subsequent increases in tau pathology and arrest related functional decline. Conclusions: This two-step approach demonstrates the importance of selecting assays most sensitive to the phenotype of the model. A robust relationship was observed between pathological progression, development of phenotype, and their experimental manipulation-three crucial factors for assessing the translational relevance of future pre-clinical findings.
doi:10.1186/s13195-017-0306-2 pmid:28931441 pmcid:PMC5607580 fatcat:tcvs236zkbfqzjc5lcztiaykni

Impaired glymphatic function and clearance of tau in an Alzheimer's disease model

Ian F Harrison, Ozama Ismail, Asif Machhada, Niall Colgan, Yolanda Ohene, Payam Nahavandi, Zeshan Ahmed, Alice Fisher, Soraya Meftah, Tracey K Murray, Ole P Ottersen, Erlend A Nagelhus (+3 others)
2020 Brain  
The glymphatic system, that is aquaporin 4 (AQP4) facilitated exchange of CSF with interstitial fluid (ISF), may provide a clearance pathway for protein species such as amyloid-β and tau, which accumulate in the brain in Alzheimer's disease. Further, tau protein transference via the extracellular space, the compartment that is cleared by the glymphatic pathway, allows for its neuron-to-neuron propagation, and the regional progression of tauopathy in the disorder. The glymphatic system therefore
more » ... represents an exciting new target for Alzheimer's disease. Here we aim to understand the involvement of glymphatic CSF-ISF exchange in tau pathology. First, we demonstrate impaired CSF-ISF exchange and AQP4 polarization in a mouse model of tauopathy, suggesting that this clearance pathway may have the potential to exacerbate or even induce pathogenic accumulation of tau. Subsequently, we establish the central role of AQP4 in the glymphatic clearance of tau from the brain; showing marked impaired glymphatic CSF-ISF exchange and tau protein clearance using the novel AQP4 inhibitor, TGN-020. As such, we show that this system presents as a novel druggable target for the treatment of Alzheimer's disease, and possibly other neurodegenerative diseases alike.
doi:10.1093/brain/awaa179 pmid:32705145 fatcat:va7pgbjgybf6lm2carjlss7xjq

Outbreak of Imported Seventh Pandemic Vibrio cholerae O1 El Tor, Algeria, 2018

Nabila Benamrouche, Chafika Belkader, Elisabeth Njamkepo, Sarah Sihem Zemam, Soraya Sadat, Karima Saighi, Dalila Torkia Boutabba, Faiza Mechouet, Rym Benhadj-Slimani, Fatma-Zohra Zmit, Jean Rauzier, Farid Kias (+7 others)
2022 Emerging Infectious Diseases  
participants and particularly Hamza Letlout of Public Health Facility of Tipaza and Ahlem Toua of Institut Pasteur of d'Algérie, Annex of Oran, for sending stool samples or Vibrio cholerae strains and Abdelali Meftah  ... 
doi:10.3201/eid2806.212451 pmid:35608654 pmcid:PMC9155889 fatcat:ry4nqfkmxfes5mteaj4jre2byu

Congrès International Valorisation des Bio ressources : Application et Impact sur le Développement Durable

2019 North African Journal of Food and Nutrition Research  
OPTIMISATION 023 PAR LA METHODOLOGIE DES SURFACES DE REPONSE DE L'HYDROLYSE DE LA BIOMASSE LIGNOCELLULOSIQUE DE L'OPUNTIA FICUS INDICAPOUR LA PRODUCTION D'ACIDE LACTIQUE DERABLI Besma 1 *, HAMMADOUCHE Sihem 1 , MEFTAH  ...  Tunisia. * Kais.rtibi@isbb.rnu.tn Key words: whey, carob powder, rabbit, potentially favorable, performance, health. 141 ETUDE DE LA QUALITE DES HUILES D'OLIVE DE LA WILAYA DE BOUMERDES YOUYOU Soraya  ... 
doi:10.51745/najfnr.3.6.a1-a127 fatcat:afzqn533ovbyxos2e6nbeffw3y