Aims

Early brain dysfunctions found in Alzheimer's disease (AD) are due to soluble pathological forms of b-amyloid peptide (Aβ). Although familial mutation-induced phenotypes are identified in AD patients, the in vivo effects of different Aβ variants are poorly understood. Here we characterized the effects of different Aβ variants on amyloid induction in a transgenic mouse model.

Methods

We produced well-characterized amyloid variants: Aβ1-42, Aβ bearing the Icelandic mutation (A2T) or the Osaka mutation (E22D[1]). Then, two-month-old APP/PS1dE9 mice were inoculated with these variants in the dentate gyrus (n=6/per group). At 4 months post-inoculation, behavioral tests and functional brain connectivity (FC) study was performed. We assessed Aβ oligomerization profiles and cerebral amyloid load.

[1] Tomiyama et al., Ann Neurol, 2008

Results

Wild type and Osaka-Aβ induced memory impairment (Fig. A) and loss of FC in mice hippocampus (Fig. B). Also, it led to increased 6-mer and 12-mer amyloid forms at inoculation site (Fig. C) but also at distance in the cortex. This suggests that Aβ variants differently modulate Aβ metabolism and aggregation. Amyloid plaque assessment showed an Osaka-Aβ-induced increase in amyloid load in the hippocampus (Fig. D) and its connected regions.

Conclusions

A single inoculation of different Aβ variants in APP/PS1dE9 mice expressing wild type Aβ is sufficient to modulate cognitive decline, Aβ forms occurrence and amyloid load. This suggests that Aβ variants specifically interact with the cerebral environments to induce different toxic downstream events.