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Abstract
BackgroundThe 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-β (Aβ) 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 Aβ 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.ResultsWe performed partial unilateral ibotenic acid lesions of the subiculum (first structure affected by Aβ pathology) in young Tg APParc mice, prior to the onset of pathology. We assessed Aβ/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 Aβ/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, Aβ/C99 pathology was unchanged in the contralateral hippocampus in the mice with lesions.ConclusionThese results, obtained in an animal model of AD, support the notion that Aβ/C99 pathology is transmitted between interconnected neurons in AD.
Highlights
The progressive development of Alzheimer’s disease (AD) pathology follows a spatiotemporal pattern in the human brain
The present study explores whether a lesion of the subiculum, achieved by injection of the excitotoxin ibotenic acid, can interrupt the spreading of Aβ pathology in Tg APParc mice which models the progressive spread of Aβ pathology over time (Figure 1)
In Tg APParc mice with lesions of the subiculum (Tg + Wild type with ibotenic injection (Ibo)), the Aβ pathology was significantly reduced in the dorsal subiculum and CA1 ipsilateral to the lesion compared to Tg APParc mice injected with Transgenic with phosphate buffered solution injection (PBS) (Tg + PBS, *p < 0.05, Figure 2C)
Summary
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. The misfolded protein pathology can spread via anatomic connections, presumably through a prion-like intercellular transfer [1,7,8,9,10,11] This mechanism could explain the stereotypic pattern of spreading of amyloid and tauopathy in the AD brain suggested by Braak and others [12,13,14,15,16,17,18]. The aim of this study is to test the hypothesis that disease-associated proteins transfer between anatomical regions in the brain and promote gradual spreading of neuropathology in a unique mouse model of AD, recapitulating the spatial and temporal development of Aβ pathology in vivo. This study supports the transmissibility of Aβ pathology between interconnected brain regions in Tg APParc mice
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