RT Journal Article
T1 Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis
A1 Sanchez-Varo, Raquel
A1 Sanchez-Mejias, Elisabeth
A1 Fernandez-Valenzuela, Juan Jose
A1 De Castro, Vanessa
A1 Mejias-Ortega, Marina
A1 Gomez-Arboledas, Angela
A1 Jimenez, Sebastian
A1 Sanchez-Mico, Maria Virtudes
A1 Trujillo-Estrada, Laura
A1 Moreno-Gonzalez, Ines
A1 Baglietto-Vargas, David
A1 Vizuete, Marisa
A1 Davila, Jose Carlos
A1 Vitorica, Javier
A1 Gutierrez, Antonia
K1 Alzheimer’s disease
K1 Synaptic pathology
K1 Hippocampus
K1 Transgenic mice (Tg)
K1 Amyloid
K1 Oligomers
K1 Enfermedad de Alzheimer
K1 Hipocampo
K1 Ratones transgénicos
K1 Amiloide
K1 Morfolinos
AB Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by initial memory impairments that progress to dementia. In this sense, synaptic dysfunction and loss have been established as the pathological features that best correlate with the typical early cognitive decline in this disease. At the histopathological level, post mortem AD brains typically exhibit intraneuronal neurofibrillary tangles (NFTs) along with the 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. In terms of losing synaptic proteins, 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 disease stages. Electron immunogold labeling showed that the periphery of amyloid 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. Indeed, this preclinical transgenic model could 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 http://hdl.handle.net/10668/4098
UL http://hdl.handle.net/10668/4098
LA en
NO Sanchez-Varo R, Sanchez-Mejias E, Fernandez-Valenzuela JJ, De Castro V, Mejias-Ortega M, Gomez-Arboledas A, et al. Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis. Front Neurosci. 2021 Nov 4;15:752594.
DS RISalud
RD Apr 7, 2025