RT Journal Article
T1 Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis
A1 Sánchez-Varo, Raquel María
A1 Sánchez-Mejías, Elisabeth
A1 Fernández-Valenzuela, Juan José
A1 De Castro Carratalá, Vanessa
A1 Mejías-Ortega, Marina
A1 Gómez-Arboledas, Ángela
A1 Jimenez, Sebastian
A1 Sanchez-Mico, Maria Virtudes
A1 Trujillo-Estrada, Laura Isabel
A1 Moreno-González, Inés
A1 Baglietto-Vargas, David
A1 Vizuete, Marisa
A1 Dávila-Cansino, José Carlos
A1 Vitorica Ferrández, Javier
A1 Gutiérrez-Pérez, Antonia
AB Synaptic dysfunction and loss have been established as the pathological features that best correlate with the early cognitive decline in Alzheimer’s disease (AD). At the histopathological level, post mortem AD brains exhibit intraneuronal neurofibrillary tangles (NFTs) and accumulation of amyloid-beta (Abeta) peptides in the form of extracellular deposits. Specifically, the oligomeric soluble forms of Abeta are considered the most synaptotoxic species. In addition, neuritic plaques are Abeta deposits surrounded by activated microglia and astroglia cells together with abnormal swellings of neuronal processes named dystrophic neurites. These periplaque aberrant neurites are mostly presynaptic elements and represent the first pathological indicator of synaptic dysfunction. The hippocampus is one of the brain regions most affected in AD patients. In this work, we report an early decline in spatial memory, along with hippocampal synaptic changes, in an amyloidogenic APP/PS1 transgenic model. Quantitative electron microscopy revealed a spatial synaptotoxic pattern around neuritic plaques with significant loss of periplaque synaptic terminals, showing rising synapse loss close to the border, especially in larger plaques. Moreover, dystrophic presynapses were filled with autophagic vesicles in detriment of the presynaptic vesicular density, probably interfering with synaptic function at very early synaptopathological stages. Electron immunogold labeling showed that the periphery of plaques, and the associated dystrophic neurites, was enriched in Abeta oligomers supporting an extracellular location of the synaptotoxins. Finally, the incubation of primary neurons with soluble fractions derived from 6-month-old APP/PS1 hippocampus induced significant loss of synaptic proteins, but not neuronal death. This preclinical transgenic model may serve to investigate therapies targeted at initial stages of synaptic dysfunction relevant to the prodromal and early AD.
PB Frontiers
YR 2021
FD 2021-11-04
LK https://hdl.handle.net/10630/28961
UL https://hdl.handle.net/10630/28961
LA eng
NO Sanchez-Varo R, Sanchez-Mejias E, Fernandez-Valenzuela JJ, De Castro V, Mejias-Ortega M, Gomez-Arboledas A, Jimenez S, Sanchez-Mico MV, Trujillo-Estrada L, Moreno-Gonzalez I, Baglietto-Vargas D, Vizuete M, Davila JC, Vitorica J, Gutierrez A. Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis. Front Neurosci. 2021 Nov 4;15:752594. doi: 10.3389/fnins.2021.752594. PMID: 34803589; PMCID: PMC8600261.
NO Copyright de los autores
NO Financiado por Instituto de Salud Carlos III (ISCiii), co-financiado por fondos FEDER de la Unión Europea. Proyectos FIS PI18/01557 y PI18/01556. Junta de Andalucía Consejería de Economía y Conocimiento proyecto UMA18-FEDERJA211, P18-RT-2233  y US-1262734. Cofinanciado por Programa Operativo FEDER2014–2020; proyecto de Ministerio de Educación y Ciencia PID2019-108911RA-100, programa Beatriz Galindo BAGAL18/00052, PID2019-107090RA-I00 y programa Ramon y Cajal  RYC-2017-21879; proyectos de la Universidad de Málaga B1-2019_07 y B1-2019_06.
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 20 ene 2026