Sustained Hippocampal Neural Plasticity Questions the Reproducibility of an Amyloid-β-Induced Alzheimer's Disease Model

Background: The use of Alzheimer's disease (AD) models obtained by intracerebral infusion of amyloid-beta (A beta) has been increasingly reported in recent years. Nonetheless, these models may present important challenges. Objective: We have focused on canonical mechanisms of hippocampal-related neural plasticity to characterize a rat model obtained by an intracerebroventricular (icv) injection of soluble amyloid-C-42 (A beta(42)). Methods: Animal behavior was evaluated in the elevated plus maze, Y-Maze spontaneous or forced alternation, Morris water maze, and open field, starting 2 weeks post-A beta(42) infusion. Hippocampal neurogenesis was assessed 3 weeks after A beta(42) injection. A beta deposition, tropomyosin receptor kinase B levels, and neuroinflammation were appraised at 3 and 14 days post-A beta(42) administration. Results: We found that immature neuronal dendritic morphology was abnormally enhanced, but proliferation and neuronal differentiation in the dentate gyrus was conserved one month after A beta(42) injection. Surprisingly, animal behavior did not reveal changes in cognitive performance nor in locomotor and anxious-related activity. Brain-derived neurotrophic factor related-signaling was also unchanged at 3 and 14 days post-A beta icv injection. Likewise, astrocytic and microglial markers of neuroinflammation in the hippocampus were unaltered in these time points. Conclusion: Taken together, our data emphasize a high variability and lack of behavioral reproducibility associated with these A beta injection-based models, as well as the need for its further optimization, aiming at addressing the gap between preclinical AD models and the human disorder.

Automated summary

The study focused on a rat model of Alzheimer's disease obtained by intracerebroventricular injection of soluble amyloid-C-42 (A beta(42)), and found that immature neuronal dendritic morphology was abnormally enhanced one month after injection. Surprisingly, there were no changes in cognitive performance or locomotor and anxious-related activity in the animal behavior tests.