| First Author | Célestine M | Year | 2023 |
| Journal | Acta Neuropathol Commun | Volume | 11 |
| Issue | 1 | Pages | 66 |
| PubMed ID | 37087498 | Mgi Jnum | J:353334 |
| Mgi Id | MGI:7467606 | Doi | 10.1186/s40478-023-01559-0 |
| Citation | Celestine M, et al. (2023) Long term worsening of amyloid pathology, cerebral function, and cognition after a single inoculation of beta-amyloid seeds with Osaka mutation. Acta Neuropathol Commun 11(1):66 |
| abstractText | Alzheimer's disease (AD) is characterized by intracerebral deposition of abnormal proteinaceous assemblies made of amyloid-beta (Ass) peptides or tau proteins. These peptides and proteins induce synaptic dysfunctions that are strongly correlated with cognitive decline. Intracerebral infusion of well-defined Abeta seeds from non-mutated Abeta(1-40) or Abeta(1-42) peptides can increase Abeta 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 Abeta peptides with different structures. The Abeta Osaka (Abeta(osa) mutation (E693Delta)) is located within the Abeta sequence and thus the Abeta(osa) peptides have different structures and properties as compared to non-mutated Abeta(1-42) peptides (Abeta(wt)). Here, we wondered if a single exposure to this mutated Abeta 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 Abeta(1-42)-bearing Osaka mutation (Abeta(osa)) in the dentate gyrus of APP(swe)/PS1(dE9) 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. Abeta pathology as well as synaptic density were evaluated by histology. The impact of Abeta(osa) peptides on synaptic health was also measured on primary cortical neurons. Remarkably, the intracerebral administration of Abeta(osa) induced cognitive and synaptic impairments as well as a reduction of functional connectivity between different brain regions, 4 months post-inoculation. It increased Abeta plaque depositions and increased Abeta oligomers. This is the first study showing that a single, sporadic event as Abeta(osa) inoculation can worsen the fate of the pathology and clinical outcome several months after the event. It suggests that a single inoculation of Abeta regulates a large cascade of events for a long time. |
