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Abnormal accumulation of autophagic vesicles correlates with axonal and synaptic pathology in young Alzheimer’s mice hippocampus

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Abnormal accumulation of autophagic vesicles correlates with axonal and synaptic pathology in young Alzheimer’s mice hippocampus

dc.contributor.author	Sanchez-Varo, Raquel	es_ES
dc.contributor.author	Trujillo-Estrada, Laura	es_ES
dc.contributor.author	Sanchez-Mejias, Elisabeth	es_ES
dc.contributor.author	Torres, Manuel	es_ES
dc.contributor.author	Baglietto-Vargas, David	es_ES
dc.contributor.author	Moreno-Gonzalez, Ines	es_ES
dc.contributor.author	De Castro, Vanessa	es_ES
dc.contributor.author	Jimenez, Sebastian	es_ES
dc.contributor.author	Ruano, Diego	es_ES
dc.contributor.author	Vizuete, Marisa	es_ES
dc.contributor.author	Davila, Jose Carlos	es_ES
dc.contributor.author	García Verdugo, José Manuel	es_ES
dc.contributor.author	Jimenez, Antonio Jesus	es_ES
dc.contributor.author	Vitorica, Javier	es_ES
dc.contributor.author	Gutierrez, Antonia	es_ES
dc.date.accessioned	2015-06-22T09:52:41Z
dc.date.available	2015-06-22T09:52:41Z
dc.date.issued	2012	es_ES
dc.identifier.citation	Acta Neuropathologica Vol. 123 Issue 1: pp. 53-70	es_ES
dc.identifier.uri	http://hdl.handle.net/10550/44683
dc.description.abstract	Dystrophic neurites associated with amyloid plaques precede neuronal death and manifest early in Alzheimer’s disease (AD). In this work we have characterized the plaque-associated neuritic pathology in the hippocampus of young (4- to 6-month-old) PS1M146L/APP751SL mice model, as the initial degenerative process underlying functional disturbance prior to neuronal loss. Neuritic plaques accounted for almost all fibrillar deposits and an axonal origin of the dystrophies was demonstrated. The early induction of autophagy pathology was evidenced by increased protein levels of the autophagosome marker LC3 that was localized in the axonal dystrophies, and by electron microscopic identification of numerous autophagic vesicles filling and causing the axonal swellings. Early neuritic cytoskeletal defects determined by the presence of phosphorylated tau (AT8-positive) and actin–cofilin rods along with decreased levels of kinesin-1 and dynein motor proteins could be responsible for this extensive vesicle accumulation within dystrophic neurites. Although microsomal Aβ oligomers were identified, the presence of A11-immunopositive Aβ plaques also suggested a direct role of plaque-associated Aβ oligomers in defective axonal transport and disease progression. Most importantly, presynaptic terminals morphologically disrupted by abnormal autophagic vesicle buildup were identified ultrastructurally and further supported by synaptosome isolation. Finally, these early abnormalities in axonal and presynaptic structures might represent the morphological substrate of hippocampal dysfunction preceding synaptic and neuronal loss and could significantly contribute to AD pathology in the preclinical stages.	es_ES
dc.subject	PS1/APP transgenic mice	es_ES
dc.subject	Dystrophic neurites	es_ES
dc.subject	Electron microscopy	es_ES
dc.subject	LC3	es_ES
dc.subject	Amyloid plaques	es_ES
dc.subject	Presynaptic terminals	es_ES
dc.title	Abnormal accumulation of autophagic vesicles correlates with axonal and synaptic pathology in young Alzheimer’s mice hippocampus	es_ES
dc.type	journal article	es_ES
dc.identifier.doi	10.1007/s00401-011-0896-x	es_ES
dc.identifier.idgrec	076893	es_ES