Long term worsening of Alzheimer pathology and clinical outcome by a single inoculation of mutated beta-amyloid seeds

Abstract

Abstract Background Alzheimer’s disease (AD) is characterized by intracerebral accumulation of abnormal proteinaceous assemblies made of amyloid-β (Aß) peptides or tau proteins. These lesions induce synaptic dysfunctions that are strongly correlated with cognitive decline. Intracerebral infusion of well-defined Aβ seeds from synthetic or recombinant non-mutated Aβ1−40 or Aβ1−42 peptides can increase Aβ plaque 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 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 compared to non-mutated Aβ. Method 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. The inoculated mice were analyzed at 4 months post-inoculation by cognitive evaluation and functional MRI to assess cerebral connectivity. Aβ and tau lesions as well as synaptic density were evaluated by histology. The impact of Aβosa peptides on synaptic health was also measured on primary cortical neurons. Results Remarkably, compared to Aβwt, the intracerebral administration of Aβosa induced cognitive impairments, synaptic impairments and a reduction of the connectivity between different brain regions, 4 months post-inoculation. Aβ plaque depositions but not tau lesions were increased and Aβ oligomeric patterns were modified. Conclusion This is the first study showing long-term functional toxicity of Aβ seeds. It shows that a single, sporadic event as Aβosa inoculation can worsen the fate of the pathology and clinical outcome several months after the event. Extrapolation of this discovery suggests that any event that modulates focally Aβ aggregation process in the time-course of AD can be responsible for the heterogeneity of AD clinical outcome.