Lesion of the subiculum reduces the spread of amyloid beta pathology to interconnected brain regions in a mouse model of Alzheimer's disease

Background: The progressive development of Alzheimer's disease (AD) pathology follows a spatiotemporal pattern in the human brain. In a transgenic (Tg) mouse model of AD expressing amyloid precursor protein (APP) with the arctic (E693G) mutation, pathology spreads along anatomically connected structures. Amyloid-beta (A beta)pathology first appears in the subiculum and is later detected in interconnected brain regions, including the retrosplenial cortex. We investigated whether the spatiotemporal pattern of A beta pathology in the Tg APP arctic mice to interconnected brain structures can be interrupted by destroying neurons using a neurotoxin and thereby disconnecting the neural circuitry. Results: We performed partial unilateral ibotenic acid lesions of the subiculum (first structure affected by A beta pathology) in young Tg APParc mice, prior to the onset of pathology. We assessed A beta/C99 pathology in mice aged up to 6 months after injecting ibotenate into the subiculum. Compared to the brains of intact Tg APP arctic mice, we observed significantly decreased A beta/C99 pathology in the ipsilateral dorsal subiculum, CA1 region of the hippocampus and the retrosplenial cortex; regions connecting to and from the dorsal subiculum. By contrast, A beta/C99 pathology was unchanged in the contralateral hippocampus in the mice with lesions. Conclusion: These results, obtained in an animal model of AD, support the notion that A beta/C99 pathology is transmitted between interconnected neurons in AD.