The molecular mechanism of gamma-aminobutyric acid against AD: the role of CEBP alpha/circAPLP2/miR-671-5p in regulating CNTN1/2 expression

The expression levels of the synaptic-related proteins contactin 1/2 (CNTN1/2) are down-regulated in the brain of Alzheimer's disease (AD), but the mechanism has not been clarified. gamma-Aminobutyric acid (GABA) is considered a biologically active ingredient in food. Our previous research revealed that GABA can regulate CEBP alpha expression in A beta-treated U251 cells. However, it is uncertain whether GABA can antagonize the pathogenesis of AD. Whether GABA can inhibit the reduction in CNTN1/2 expression by regulating CEBP alpha/circAPLP2/miR-671-5p in the AD brain remains unclear yet. Here, we demonstrate that GABA could attenuate the deposition of A beta in the brain and ameliorate cognitive impairments in AD model mice. The expressions of CEBP alpha, circAPLP2, and CNTN1/2 were decreased and that of miR-671-5p was increased in AD model mouse brains and A beta-induced SH-SY5Y cells. These alterations were partly reversed by GABA. The CNTN1/2 expression was down-regulated and up-regulated in SH-SY5Y cells treated with miR-671-5p mimics and miR-671-5p inhibitors, respectively. The results from the luciferase reporter assay revealed that miR-671-5p could bind to the 3 '-untranslated region of circAPLP2. The silencing of circAPLP2 with the siRNA duplex caused an up-regulation of miR-671-5p and a down-regulation of CNTN1/2 in SH-SY5Y cells. The silencing of CEBP alpha with the siRNA duplex caused a down-regulation of circAPLP2 or CNTN1/2 and an up-regulation of miR-671-5p. In conclusion, GABA may decrease the deposition of A beta in the brain, inhibit the down-regulation of CNTN1/2 expression, and ameliorate the cognitive deficits of AD model mice. The CEBP alpha/circAPLP2/miR-671-5p pathway plays a role in regulating CNTN1/2 expression by GABA in AD.