Decreased generation of C‐terminal fragments of ApoER2 and increased reelin expression in Alzheimer's disease

Increasing evidence indicates that altered reelin signaling could contribute to synaptic dysfunction in Alzheimer's disease (AD). We found that reelin protein and mRNA levels were increased in the AD brain (particularly at advanced Braak stages in apolipoprotein E4 noncarriers), compared with that of control subjects. The β‐amyloid (Aβ) protein impairs reelin activity and increases reelin expression through a mechanism that is not yet understood. To explore that mechanism, we examined the effect of Aβ aa 1–42 (Aβ 42 ) on DNA methylation of the RELN promoter and the processing of reelin receptor apolipoprotein E receptor 2 (ApoER2) in differentiated SH‐SY5Y cells because ApoER2 C‐terminal fragments (CTFs), generated after reelin binding, regulate reelin expression. We found that Aβ 42 decreased nuclear levels of DNA‐methyltransferase 1. However, RELN promoter methylation did not change in Aβ 42 ‐ treated cells or in AD brain extracts. Instead, the levels of ApoER2‐CTF appeared significantly lower in Aβ 42 ‐treated cells and in AD extracts from advanced Braak stages of apolipoprotein E4 noncarriers. Our data show that ApoER2‐ CTF levels are decreased, whereas reelin expression is increased in AD brain at advanced Braak stages and after Aβ treatment, supporting the view that ApoER2‐CTF exerts a modulatory role on reelin expression.—Mata‐Balaguer, T., Cuchillo‐Ibañez, I., Calero, M., Ferrer, I., Sáez‐Valero, J. Decreased generation of C‐terminal fragments of ApoER2 and increased reelin expression in Alzheimer's disease. FASEB J. 32, 3536–3546 (2018). www.fasebj.org