Interneurons in the CA1 stratum oriens expressing αTTP may play a role in the delayed-ageing Pol μ mouse model

Abstract

Neurodegeneration associated with ageing is closely linked to oxidative stress (OS) and disrupted calcium homeostasis. Some areas of the brain, like the hippocampus – particularly the CA1 region – have shown a high susceptibility to age-related changes, displaying early signs of pathology and neuronal loss. Antioxidants such as α-tocopherol (αT) have been effective in mitigating the impact of OS during ageing. αT homeostasis is primarily regulated by the α-tocopherol transfer protein (αTTP), which is widely distributed throughout the brain – where it plays a crucial role in maintaining αT levels within neuronal cells.

This study investigates the distribution of αTTP in the hippocampus of 4- and 24-month-old Pol μ knockout mice (Pol μ^−/−), a delayed-ageing model, and the wild type (Pol μ^+/+). We also examine the colocalisation in the stratum oriens (st.or) of CA1 region with the primary interneuron populations expressing calcium-binding proteins (CBPs) (calbindin (CB), parvalbumin (PV), and calretinin (CR)). Our findings reveal that αTTP immunoreactivity (-IR) in the st.or of Pol μ mice is significantly reduced. The density of PV-expressing interneurons (INs) increased in aged mice in both Pol μ genotypes (Pol μ^−/− and Pol μ^+/+), although the density of PV-positive INs was lower in the aged Pol μ^−/− mice compared to wild-type mice. By contrast, CR- and CB-positive INs in Pol μ mice remained unchanged during ageing.

Furthermore, double immunohistochemistry reveals the colocalisation of αTTP with CBPs in INs of the CA1 st.or. Our study also shows that the PV/αTTP-positive IN population remains unchanged in all groups. A significant decrease of CB/αTTP-positive INs in young Pol μ^−/− mice has been detected, as well as a significant increase in CR/αTTP-IR in older Pol μ^−/− animals. These results suggest that the differential expression of αTTP and CBPs could have a crucial effect in aiding the survival and maintenance of the different IN populations in the CA1 st.or, and their coexpression could contribute to the enhancement of their resistance to OS-related damage and neurodegeneration associated with ageing.