Transmissible long-term neuroprotective and pro-cognitive effects of 1-42 beta-amyloid with A2T icelandic mutation in...

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 (Aβ_ice). In addition, Aβ_ice has the capacity to form protective heterodimers in association with wild-type Aβ. Despite the emerging interest in Aβ_ice during the last decade, the impact of Aβ_ice on events associated with the amyloid cascade has never been reported. First, the effects of Aβ_ice were evaluated in vitro by electrophysiology on hippocampal slices and by studying synapse morphology in cortical neurons. We showed that Aβ_ice 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 Aβ_ice or Aβ-wild-type (Aβ_wt) in the hippocampus of transgenic mice (APP_swe/PS1_dE9) over-expressing Aβ_1-42 peptide. Interestingly, we found that the single intra-hippocampal inoculation of Aβ_ice to mice rescued synaptic density and spatial memory losses four months post-inoculation, compared with Aβ_wt inoculation. Although Aβ load was not modulated by Aβ_ice infusion, the amount of Tau-positive neuritic plaques was significantly reduced. Finally, a lower phagocytosis by microglia of post-synaptic compounds was detected in Aβ_ice-inoculated animals, which can partly explain the increased density of synapses in the Aβ_ice animals. Thus, a single event as Aβ_ice 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.