1. Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis
- Author
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Raquel Sanchez-Varo, Elisabeth Sanchez-Mejias, Juan Jose Fernandez-Valenzuela, Vanessa De Castro, Marina Mejias-Ortega, Angela Gomez-Arboledas, Sebastian Jimenez, Maria Virtudes Sanchez-Mico, Laura Trujillo-Estrada, Ines Moreno-Gonzalez, David Baglietto-Vargas, Marisa Vizuete, Jose Carlos Davila, Javier Vitorica, Antonia Gutierrez, Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Ministerio de Ciencia e Innovación (España), Universidad de Málaga, [Sanchez-Varo,R, Sanchez-Mejias,E, Fernandez-Valenzuela,JJ, De Castro,V, Mejias-Ortega,M, Gomez-Arboledas,A, Trujillo-Estrada,L, Moreno-Gonzalez,I, Baglietto-Vargas,D, Davila,JC, Gutierrez,A] Departamento Biologia Celular, Genetica y Fisiologia, Instituto de Investigacion Biomedica de Malaga-IBIMA, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain. [Sanchez-Varo,R, Jimenez,S, Sanchez-Mico,MV, Vizuete,M, Vitorica,J, Gutierrez,A] Centro de Investigación Biomedica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. [Sanchez-Varo,R] Departamento Fisiologia Humana, Histologia Humana, Anatomia Patologica y Educacion Fisica y Deportiva, Facultad de Medicina, Universidad de Málaga, Málaga, Spain. [Jimenez,S, Vitorica,J] Departamento Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain. [Jimenez,S, Vitorica,J] Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio CSIC/Universidad de Sevilla, Seville, Spain. [Moreno-Gonzalez,I] Department of Neurology, McGovern Medical School, UTHealth Science Center at Houston, Houston, TX, United States, This study was supported by the Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by the FEDER funds from European Union, through grants PI18/01557 (to AG) and PI18/01556 (to JV), by the Junta de Andalucia Consejería de Economía y Conocimiento through grants UMA18-FEDERJA-211 (to AG), P18-RT-2233 (to AG), and US-1262734 (to JV) co-financed by Programa Operativo FEDER 2014–2020, by the Spanish Minister of Science and Innovation grant PID2019-108911RA-100 (to DB-V), Beatriz Galindo program BAGAL18/00052 (to DB-V) grant PID2019-107090RA-I00 (to IM-G), and Ramon y Cajal Program RYC-2017-21879 (to IM-G), and and by the Malaga University grants B1-2019_07 (to ES-M) and B1-2019_06 (to IM-G). MM-O held a predoctoral contract from Malaga University and ES-M a postdoctoral contract (DOC_00251) from Junta de Andalucia.
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Amyloid ,Diseases::Nervous System Diseases::Neurodegenerative Diseases::Tauopathies::Alzheimer Disease [Medical Subject Headings] ,Amyloid beta ,hippocampus ,Anatomy::Nervous System::Neuroglia::Astrocytes [Medical Subject Headings] ,Hippocampus ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Hippocampal formation ,Anatomy::Nervous System::Neuroglia::Microglia [Medical Subject Headings] ,Ratones transgénicos ,Synapse ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,Anatomy::Nervous System::Neurons::Neurofibrils::Neurofibrillary Tangles [Medical Subject Headings] ,Transgenic mice (Tg) ,Enfermedad de Alzheimer ,Diseases::Pathological Conditions, Signs and Symptoms::Pathological Conditions, Anatomical::Plaque, Amyloid [Medical Subject Headings] ,medicine ,Hipocampo ,Anatomy::Nervous System::Central Nervous System::Brain::Limbic System::Hippocampus [Medical Subject Headings] ,Senile plaques ,Cognitive decline ,oligomers ,Original Research ,Persons::Persons::Age Groups::Infant [Medical Subject Headings] ,synaptic pathology ,biology ,Microglia ,Anatomy::Nervous System::Neurons::Nerve Fibers::Axons::Neurites [Medical Subject Headings] ,Amiloide ,General Neuroscience ,Morfolinos ,amyloid ,Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings] ,Phenomena and Processes::Physical Phenomena::Elementary Particles::Electrons [Medical Subject Headings] ,medicine.anatomical_structure ,Oligomers ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Imaging::Microscopy::Microscopy, Electron [Medical Subject Headings] ,biology.protein ,Neuroscience ,Alzheimer’s disease ,Synaptic pathology ,Anatomy::Nervous System::Synapses::Presynaptic Terminals [Medical Subject Headings] ,transgenic mice (Tg) ,RC321-571 - Abstract
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., This study was supported by the Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by the FEDER funds from European Union, through grants PI18/01557 (to AG) and PI18/01556 (to JV); by the Junta de Andalucia Consejería de Economía y Conocimiento through grants UMA18-FEDERJA-211 (to AG), P18-RT-2233 (to AG), and US-1262734 (to JV) co-financed by Programa Operativo FEDER 2014–2020; by the Spanish Minister of Science and Innovation grant PID2019-108911RA-100 (to DB-V), Beatriz Galindo program BAGAL18/00052 (to DB-V) grant PID2019-107090RA-I00 (to IM-G), and Ramon y Cajal Program RYC-2017-21879 (to IM-G); and by the Malaga University grants B1-2019_07 (to ES-M) and B1-2019_06 (to IM-G). MM-O held a predoctoral contract from Malaga University and ES-M a postdoctoral contract (DOC_00251) from Junta de Andalucia.
- Published
- 2021