Altered Clock Gene Expression in Female APP/PS1 Mice and Aquaporin-Dependent Amyloid Accumulation in the Retina

Abstract

Alzheimer’s disease (AD), the most prevalent form of dementia, is a neurodegenerative disorder characterized by different pathological symptomatology, including disrupted circadian rhythm. The regulation of circadian rhythm depends on the light information that is projected from the retina to the suprachiasmatic nucleus in the hypothalamus. Studies of AD patients and AD transgenic mice have revealed AD retinal pathology, including amyloid-β (Aβ) accumulation that can directly interfere with the regulation of the circadian cycle. Although the cause of AD pathology is poorly understood, one of the main risk factors for AD is female gender. Here, we found that female APP/PS1 mice at 6- and 12-months old display severe circadian rhythm disturbances and retinal pathological hallmarks, including Aβ deposits in retinal layers. Since brain Aβ transport is facilitated by aquaporin (AQP)4, the expression of AQPs were also explored in APP/PS1 retina to investigate a potential correlation between retinal Aβ deposits and AQPs expression. Important reductions in AQP1, AQP4, and AQP5 were detected in the retinal tissue of these transgenic mice, mainly at 6-months of age. Taken together, our findings suggest that abnormal transport of Aβ, mediated by impaired AQPs expression, contributes to the retinal degeneration in the early stages of AD.

Special Issue “Aquaporins in Brain Disease”

“…Consistent with this, the disruption of circadian rhythms has also been indicated among the different pathological symptoms of AD. The work of Carrero et al [ 3 ] demonstrates an important reduction in the expression of AQP1, AQP4, and AQP5 in the retinal tissue of APP/PS1 mice, an animal model of Alzheimer’s disease. In these animals, the accumulation of amyloid B (AB) was also observed, which directly interferes with light information projected from the retina to the suprachiasmatic nucleus in the hypothalamus, thus affecting the regulation of the circadian rhythm.…”