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  • Title: Transmissible long-term neuroprotective and pro-cognitive effects of 1-42 beta-amyloid with A2T icelandic mutation in an Alzheimer's disease mouse model.
    Author: Célestine M, Jacquier-Sarlin M, Borel E, Petit F, Lante F, Bousset L, Hérard AS, Buisson A, Dhenain M.
    Journal: Mol Psychiatry; 2024 Dec; 29(12):3707-3721. PubMed ID: 38871852.
    Abstract:
    The amyloid cascade hypothesis assumes that the development of Alzheimer's disease (AD) is driven by a self-perpetuating cycle, in which β-amyloid (Aβ) accumulation leads to Tau pathology and neuronal damages. A particular mutation (A673T) of the amyloid precursor protein (APP) was identified among Icelandic population. It provides a protective effect against Alzheimer- and age-related cognitive decline. This APP mutation leads to the reduced production of Aβ with A2T (position in peptide sequence) change (Aβice). In addition, Aβice has the capacity to form protective heterodimers in association with wild-type Aβ. Despite the emerging interest in Aβice during the last decade, the impact of Aβice on events associated with the amyloid cascade has never been reported. First, the effects of Aβice were evaluated in vitro by electrophysiology on hippocampal slices and by studying synapse morphology in cortical neurons. We showed that Aβice protects against endogenous Aβ-mediated synaptotoxicity. Second, as several studies have outlined that a single intracerebral administration of Aβ can worsen Aβ deposition and cognitive functions several months after the inoculation, we evaluated in vivo the long-term effects of a single inoculation of Aβice or Aβ-wild-type (Aβwt) in the hippocampus of transgenic mice (APPswe/PS1dE9) over-expressing Aβ1-42 peptide. Interestingly, we found that the single intra-hippocampal inoculation of Aβice to mice rescued synaptic density and spatial memory losses four months post-inoculation, compared with Aβwt inoculation. Although Aβ load was not modulated by Aβice infusion, the amount of Tau-positive neuritic plaques was significantly reduced. Finally, a lower phagocytosis by microglia of post-synaptic compounds was detected in Aβice-inoculated animals, which can partly explain the increased density of synapses in the Aβice animals. Thus, a single event as Aβice inoculation can improve the fate of AD-associated pathology and phenotype in mice several months after the event. These results open unexpected fields to develop innovative therapeutic strategies against AD.
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