P62 accumulates through neuroanatomical circuits in response to tauopathy propagation

Abstract In Alzheimer’s disease and related tauopathies, trans-synaptic transfer and accumulation of pathological tau from donor to recipient neurons is thought to contribute to disease progression, but the underlying mechanisms are poorly understood. Using complementary in vivo and in vitro models,...

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Autores principales:	François-Xavier Blaudin de Thé, Benjamin Lassus, Ari W. Schaler, Stephanie L. Fowler, Chris N. Goulbourne, Ross Jeggo, Clotilde Mannoury la Cour, Mark J. Millan, Karen E. Duff
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Tauopathy Spread p62 Clearance Microfluidics Electron microscopy Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/6ec10d2a588a40fb82206e796520623e
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spelling	oai:doaj.org-article:6ec10d2a588a40fb82206e796520623e2021-11-07T12:17:13ZP62 accumulates through neuroanatomical circuits in response to tauopathy propagation10.1186/s40478-021-01280-w2051-5960https://doaj.org/article/6ec10d2a588a40fb82206e796520623e2021-11-01T00:00:00Zhttps://doi.org/10.1186/s40478-021-01280-whttps://doaj.org/toc/2051-5960Abstract In Alzheimer’s disease and related tauopathies, trans-synaptic transfer and accumulation of pathological tau from donor to recipient neurons is thought to contribute to disease progression, but the underlying mechanisms are poorly understood. Using complementary in vivo and in vitro models, we examined the relationship between these two processes and neuronal clearance. Accumulation of p62 (a marker of defective protein clearance) correlated with pathological tau accumulation in two mouse models of tauopathy spread; Entorhinal Cortex-tau (EC-Tau) mice where tau pathology progresses in time from EC to other brain regions, and PS19 mice injected with tau seeds. In both models and in several brain regions, p62 colocalized with human tau in a pathological conformation (MC1 antibody). In EC-Tau mice, p62 accumulated before overt tau pathology had developed and was associated with the presence of aggregation-competent tau seeds identified using a FRET-based assay. Furthermore, p62 accumulated in the cytoplasm of neurons in the dentate gyrus of EC-Tau mice prior to the appearance of MC1 positive tauopathy. However, MC1 positive tau was shown to be present at the synapse and to colocalize with p62 as shown by immuno electron microscopy. In vitro, p62 colocalized with tau inclusions in two primary cortical neuron models of tau pathology. In a three-chamber microfluidic device containing neurons overexpressing fluorescent tau, seeding of tau in the donor chamber led to tau pathology spread and p62 accumulation in both the donor and the recipient chamber. Overall, these data are in accordance with the hypothesis that the accumulation and trans-synaptic spread of pathological tau disrupts clearance mechanisms, preceding the appearance of obvious tau aggregation. A vicious cycle of tau accumulation and clearance deficit would be expected to feed-forward and exacerbate disease progression across neuronal circuits in human tauopathies.François-Xavier Blaudin de ThéBenjamin LassusAri W. SchalerStephanie L. FowlerChris N. GoulbourneRoss JeggoClotilde Mannoury la CourMark J. MillanKaren E. DuffBMCarticleTauopathySpreadp62ClearanceMicrofluidicsElectron microscopyNeurology. Diseases of the nervous systemRC346-429ENActa Neuropathologica Communications, Vol 9, Iss 1, Pp 1-19 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Tauopathy Spread p62 Clearance Microfluidics Electron microscopy Neurology. Diseases of the nervous system RC346-429
spellingShingle	Tauopathy Spread p62 Clearance Microfluidics Electron microscopy Neurology. Diseases of the nervous system RC346-429 François-Xavier Blaudin de Thé Benjamin Lassus Ari W. Schaler Stephanie L. Fowler Chris N. Goulbourne Ross Jeggo Clotilde Mannoury la Cour Mark J. Millan Karen E. Duff P62 accumulates through neuroanatomical circuits in response to tauopathy propagation
description	Abstract In Alzheimer’s disease and related tauopathies, trans-synaptic transfer and accumulation of pathological tau from donor to recipient neurons is thought to contribute to disease progression, but the underlying mechanisms are poorly understood. Using complementary in vivo and in vitro models, we examined the relationship between these two processes and neuronal clearance. Accumulation of p62 (a marker of defective protein clearance) correlated with pathological tau accumulation in two mouse models of tauopathy spread; Entorhinal Cortex-tau (EC-Tau) mice where tau pathology progresses in time from EC to other brain regions, and PS19 mice injected with tau seeds. In both models and in several brain regions, p62 colocalized with human tau in a pathological conformation (MC1 antibody). In EC-Tau mice, p62 accumulated before overt tau pathology had developed and was associated with the presence of aggregation-competent tau seeds identified using a FRET-based assay. Furthermore, p62 accumulated in the cytoplasm of neurons in the dentate gyrus of EC-Tau mice prior to the appearance of MC1 positive tauopathy. However, MC1 positive tau was shown to be present at the synapse and to colocalize with p62 as shown by immuno electron microscopy. In vitro, p62 colocalized with tau inclusions in two primary cortical neuron models of tau pathology. In a three-chamber microfluidic device containing neurons overexpressing fluorescent tau, seeding of tau in the donor chamber led to tau pathology spread and p62 accumulation in both the donor and the recipient chamber. Overall, these data are in accordance with the hypothesis that the accumulation and trans-synaptic spread of pathological tau disrupts clearance mechanisms, preceding the appearance of obvious tau aggregation. A vicious cycle of tau accumulation and clearance deficit would be expected to feed-forward and exacerbate disease progression across neuronal circuits in human tauopathies.
format	article
author	François-Xavier Blaudin de Thé Benjamin Lassus Ari W. Schaler Stephanie L. Fowler Chris N. Goulbourne Ross Jeggo Clotilde Mannoury la Cour Mark J. Millan Karen E. Duff
author_facet	François-Xavier Blaudin de Thé Benjamin Lassus Ari W. Schaler Stephanie L. Fowler Chris N. Goulbourne Ross Jeggo Clotilde Mannoury la Cour Mark J. Millan Karen E. Duff
author_sort	François-Xavier Blaudin de Thé
title	P62 accumulates through neuroanatomical circuits in response to tauopathy propagation
title_short	P62 accumulates through neuroanatomical circuits in response to tauopathy propagation
title_full	P62 accumulates through neuroanatomical circuits in response to tauopathy propagation
title_fullStr	P62 accumulates through neuroanatomical circuits in response to tauopathy propagation
title_full_unstemmed	P62 accumulates through neuroanatomical circuits in response to tauopathy propagation
title_sort	p62 accumulates through neuroanatomical circuits in response to tauopathy propagation
publisher	BMC
publishDate	2021
url	https://doaj.org/article/6ec10d2a588a40fb82206e796520623e
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P62 accumulates through neuroanatomical circuits in response to tauopathy propagation

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