LRRC4 enhances synaptic function and alleviates neuronal injury in high-fat diet mice

Obesity, a chronic metabolic disease, increases the risk of neurodegenerative disorders and cognitive impairments. Cumulative evidence reveal obesity impairs hippocampal synaptic plasticity and induces neuronal apoptosis. Leucine rich repeat containing 4 (LRRC4) is a member of the Netrin G ligand (NGL) family, and plays a crucial role in maintaining neuronal morphology, function, and structure of synapses. However, it remains unclear whether LRRC4 affects obesity-induced cognitive impairment or its underlying mechanism. Herein, we showed that a high-fat diet (HFD) led to cognitive deficits in obese mice, as assessed by the Morris water maze and Nest building tests. The expression of LRRC4 and postsynaptic dense protein 95 (PSD-95) was downregulated in the hippocampus of mice with HFD-fed obesity. Furthermore, the effects of LRRC4 overexpression (AAV-LRRC4) and knockout (Lrrc4^-/-, deletion location: 28,831,753-28,828,926) on neurological function and synapses were investigated. Data from behavioral and electrophysiological studies demonstrated that LRRC4 knockout impaired synaptic plasticity and resulted in cognitive impairment in mice. Moreover, the expression level of PSD-95 was further decreased in Lrrc4^-/-mice fed by HFD. Meanwhile, the expression of the anti-apoptotic protein Bcl-2 was decreased, whereas the levels of the pro-apoptotic proteins cleaved-caspase 3 and BAX were increased in the hippocampus of HFD Lrrc4^-/- mice. This indicated that Lrrc4 knockout exacerbated neuronal injury and apoptosis. Overexpression of LRRC4 in the hippocampus of HFD mice, ameliorated the behavioral abnormalities of HFD mice and strengthened synaptic transmission. In parallel, Golgi staining displayed a significant increase in the length and number of dendritic branches of neurons. Additionally, LRRC4 overexpression promoted PSD-95 expression and exerted an anti-apoptotic effect, as evidenced by the upregulation of Bcl-2 and downregulation of cleaved caspase-3 and BAX in the hippocampus. These findings suggest that LRRC4 enhances synaptic function and alleviates neuronal injury in HFD mice. Targeting LRRC4 may have therapeutic potentiality for neurodegenerative disorders and cognitive deficits.