Beta-amyloid pathology in the entorhinal cortex of rats induces memory deficits: implications for Alzheimer's disease

Alzheimer's disease is characterized by the presence of senile plaques in the brain, composed mainly of aggregated amyloid-beta peptide (Abeta), which plays a central role in the pathogenesis of Alzheimer's disease and is a potential target for therapeutic intervention. Amyloid plaques occur in an increasing number of brain structures during the progression of the disease, with a heavy load in regions of the temporal cortex in the early phases. Here, we investigated the cognitive deficits specifically associated with amyloid pathology in the entorhinal cortex. The amyloid peptide Abeta(1-42) was injected bilaterally into the entorhinal cortex of rats and behavioral performance was assessed between 10 and 17 days after injection. We found that parameters of motor behavior in an open-field as well as spatial working memory tested in an alternation task were normal. In contrast, compared with naive rats or control rats injected with saline, rats injected with Abeta(1-42) showed impaired recognition memory in an object recognition task and delayed acquisition in a spatial reference memory task in a water-maze, despite improved performance with training in this task and normal spatial memory in a probe test given 24 h after training. This profile of behavioral deficits after injection of Abeta(1-42) into the entorhinal cortex was similar to that observed in another group of rats injected with the excitotoxic drug, N-methyl-d-aspartate. Immunohistochemical analysis after behavioral testing revealed that Abeta(1-42) injection induced a reactive astroglial response and plaque-like deposits in the entorhinal cortex. These results show that experimentally-induced amyloid pathology in the entorhinal cortex induces selective cognitive deficits, resembling those observed in early phases of Alzheimer's disease. Therefore, injection of protofibrillar-fibrillar Abeta(1-42) into the entorhinal cortex constitutes a promising animal model for investigating selective aspects of Alzheimer's disease and for screening drug candidates designed against Abeta pathology.