RT Journal Article
T1 Defective lysosomal proteolysis and axonal transport are early pathogenic events that worsen with age leading to increased APP metabolism and synaptic Abeta in transgenic APP/PS1 hippocampus.
A1 Torres, Manuel
A1 Jiménez, Sebastián
A1 Sánchez-Varo, Raquel María
A1 Navarro, Victoria
A1 Trujillo-Estrada, Laura Isabel
A1 Sánchez-Mejías, Elisabeth
A1 Carmona, Irene
A1 Dávila-Cansino, José Carlos
A1 Vizuete, Marisa
A1 Gutiérrez-Pérez, Antonia
A1 Vitorica Ferrández, Javier
K1 Alzheimer, Enfermedad de - Modelos animales
K1 Sistema nervioso - Degeneración
AB Axonal pathology might constitute one of the earliest manifestations of Alzheimer disease. Axonal dystrophies were observed in patients and transgenic models. These dystrophies could reflect the disruption of axonal transport and the accumulation of multiple vesicles at local points. Dystrophies might interfere with normal intracellular proteolysis. We have investigated the progression of the hippocampal pathology and the implication in Abeta production in young and aged PS1/APP mice. Our data demonstrated the existence of a progressive, age-dependent formation of axonal dystrophies, mainly in contact with plaques, which exhibited tau and neurofilament hyperphosphorylation. This pathology was paralleled with decreased expression of the motor proteins kinesin and dynein. Furthermore, we observed an early decrease in the activity of cathepsins B and D, progressing to a deep inhibition at late ages. This lysosomal impairment could be responsible for the accumulation of LC3-II and ubiquitinated proteins within axonal dystrophies. Our data demonstrated the existence of an increase in the amyloidogenic pathway, reflected by the accumulation of hAPPfl, C99 fragment, intracellular Abeta in parallel with an increase in secretase activities. Experiments with APPswe transfected N2a cells demonstrated that any imbalance on the proteolytic systems reproduced the in vivo alterations in APP metabolism. Finally, our data demonstrated that Abeta peptides were preferentially accumulated in isolated synaptosomes. Conclusion: A progressive age-dependent cytoskeletal pathology along with a reduction of lysosomal and proteasomal activity could be directly implicated in the progressive accumulation of APP-derived fragments (and Abeta peptides) in parallel with the increase of secretase activities. This retard in the APP metabolism seemed to be directly implicated in the synaptic Abeta accumulation and, in consequence, in the pathology progression between synaptically connected regions.
PB Springer Nature
YR 2012
FD 2012-11-22
LK https://hdl.handle.net/10630/31857
UL https://hdl.handle.net/10630/31857
LA eng
NO Torres M, Jimenez S, Sanchez-Varo R, Navarro V, Trujillo-Estrada L, Sanchez-Mejias E, Carmona I, Davila JC, Vizuete M, Gutierrez A, Vitorica J. Defective lysosomal proteolysis and axonal transport are early pathogenic events that worsen with age leading to increased APP metabolism and synaptic Abeta in transgenic APP/PS1 hippocampus. Mol Neurodegener. 2012 Nov 22;7:59. doi: 10.1186/1750-1326-7-59. PMID: 23173743; PMCID: PMC3575255.
NO Fondo de Investigación Sanitaria (Instituto de Salud Carlos III,España) ref. PS09/00151 (JV) y ref. PS09/00099 (AG).Junta de Andalucía CTS-4795 (JV) y SAS PI-0496/2009 (AG).CIBERNED ref. PI2010/08 (JV y AG). MT, SJ y RS-V contratados CIBERNED.VN beca predoctoral programa FPI. ES-M y LT-E becas predoctorales programa FPU.
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 22 ene 2026