Long term worsening of amyloid pathology, cerebral function, and cognition after a single inoculation of beta-amyloid seeds with Osaka mutation
-
Published:2023-04-22
Issue:1
Volume:11
Page:
-
ISSN:2051-5960
-
Container-title:Acta Neuropathologica Communications
-
language:en
-
Short-container-title:acta neuropathol commun
Author:
Célestine MarinaORCID, Jacquier-Sarlin Muriel, Borel Eve, Petit Fanny, Perot Jean-Baptiste, Hérard Anne-Sophie, Bousset Luc, Buisson AlainORCID, Dhenain MarcORCID
Abstract
Abstract
Alzheimer’s disease (AD) is characterized by intracerebral deposition of abnormal proteinaceous assemblies made of amyloid-β (Aß) peptides or tau proteins. These peptides and proteins induce synaptic dysfunctions that are strongly correlated with cognitive decline. Intracerebral infusion of well-defined Aβ seeds from non-mutated Aβ1-40 or Aβ1-42 peptides can increase Aβ depositions several months after the infusion. Familial forms of AD are associated with mutations in the amyloid precursor protein (APP) that induce the production of Aβ peptides with different structures. The Aβ Osaka (Aβosa mutation (E693Δ)) is located within the Aβ sequence and thus the Aβosa peptides have different structures and properties as compared to non-mutated Aβ1-42 peptides (Aβwt). Here, we wondered if a single exposure to this mutated Aβ can worsen AD pathology as well as downstream events including cognition, cerebral connectivity and synaptic health several months after the inoculation. To answer this question we inoculated Aβ1-42-bearing Osaka mutation (Aβosa) in the dentate gyrus of APPswe/PS1dE9 mice at the age of two months. Their cognition and cerebral connectivity were analyzed at 4 months post-inoculation by behavioral evaluation and functional MRI. Aβ pathology as well as synaptic density were evaluated by histology. The impact of Aβosa peptides on synaptic health was also measured on primary cortical neurons. Remarkably, the intracerebral administration of Aβosa induced cognitive and synaptic impairments as well as a reduction of functional connectivity between different brain regions, 4 months post-inoculation. It increased Aβ plaque depositions and increased Aβ oligomers. This is the first study showing that a single, sporadic event as Aβosa inoculation can worsen the fate of the pathology and clinical outcome several months after the event. It suggests that a single inoculation of Aβ regulates a large cascade of events for a long time.
Graphical Abstract
Funder
Fondation Vaincre Alzheimer Association France Alzheimer Agence Nationale de la Recherche Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology (clinical),Pathology and Forensic Medicine
Reference53 articles.
1. Abraham A, Pedregosa F, Eickenberg M, Gervais P, Mueller A, Kossaifi J, Gramfort A, Thirion B, Varoquaux G (2014) Machine learning for neuroimaging with scikit-learn. Front Neuroinform. https://doi.org/10.3389/fninf.2014.00014 2. Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T, Chiesa R, Gobbi M, Salmona M, Forloni G (2010) Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein. Proc Natl Acad Sci USA 107:2295–2300. https://doi.org/10.1073/pnas.0911829107 3. Celestine M, Nadkarni NA, Garin C, Bougacha S, Dhenain M (2020) Sammba-MRI, a library for small animal neuroimaging data processing in Python. Front Neuroinform. https://doi.org/10.3389/fninf.2020.00024 4. Dorr AE, Lerch JP, Spring S, Kabani N, Henkelman RM (2008) High resolution three-dimensional brain atlas using an average magnetic resonance image of 40 adult C57Bl/6J mice. Neuroimage 42:60–69. https://doi.org/10.1016/j.neuroimage.2008.03.037 5. du Sert NP, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, Clark A, Cuthill IC, Dirnagl U, Emerson M, Garner P, Holgate ST, Howells DW, Karp NA, Lazic SE, Lidster K, MacCallum CJ, Macleod M, Pearl EJ, Petersen OH, Rawle F, Reynolds P, Rooney K, Sena ES, Silberberg SD, Steckler T, Wurbel H (2020) The ARRIVE guidelines 20: Updated guidelines for reporting animal research. Bmc Veterinary Research. https://doi.org/10.1186/s12917-020-02451-y
|
|