Article
Abnormal accumulation of autophagic vesicles correlates with axonal and synaptic pathology in young Alzheimer’s mice hippocampus
Author/s | Sánchez Varo, Raquel María
Trujillo Estrada, Laura Isabel Sánchez Mejías, Elisabeth Torres Canalejo, Manuel Baglietto Vargas, David Moreno González, Inés Jiménez Muñoz, Sebastián Ruano Caballero, Diego Vizuete Chacón, María Luisa Vitorica Ferrández, Francisco Javier Gutiérrez Pérez, Antonia |
Department | Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular |
Publication Date | 2012 |
Deposit Date | 2022-08-12 |
Published in |
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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 ... 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 Ab oligomers were identified, the presence of A11-immunopositive Ab plaques also suggested a direct role of plaque-associated Ab 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. |
Funding agencies | Instituto de Salud Carlos III Junta de Andalucía |
Project ID. | PS09/00099
PS09/00151 PS09/00848 PS09/00376 SAS P09/496 CTS-4795 |
Citation | Sánchez Varo, R.M., Trujillo Estrada, L.I., Sánchez Mejías, E., Torres Canalejo, M., Baglietto Vargas, D., Moreno González, I.,...,Gutiérrez Pérez, A. (2012). Abnormal accumulation of autophagic vesicles correlates with axonal and synaptic pathology in young Alzheimer’s mice hippocampus. Acta Neuropathologica, 123 (1), 53-70. |
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