Hydrogen Sulfide ameliorates homocysteine-induced Alzheimer's disease-like pathology, blood brain barrier disruption and synaptic disorder

Abstract

Elevated plasma total homocysteine (Hcy) level is associated with an increased risk of Alzheimer's disease (AD). During transsulfuration pathways, Hcy is metabolized into hydrogen sulfide (H ₂S), which is a synaptic modulator, as well as a neuro-protective agent. However, the role of hydrogen sulfide, as well as NMDAR activation, in hyperhomocysteinemia (HHcy) induced blood-brain barrier (BBB) disruption and synaptic dysfunction, leading to AD pathology is not clear. Therefore, we hypothesized that the inhibition of neuronal NMDA-R by H ₂S and MK801; mitigate the Hcy-induced BBB disruption and synapse dysfunction, in part by decreasing neuronal matrix degradation. Hcy intracerebral (IC) treatment significantly impaired cerebral blood flow (CBF), and cerebral circulation and memory function. Hcy treatment also decreases the expression of CBS and CSE in the brain along with increased expression of NMDA-R (NR1) and synaptosomal Ca ²⁺ indicating excitotoxicity. Additionally, we found Hcy treatment increased protein and mRNA expression of ICAM-1, MMP-2 and MMP-9 and also increased MMP-2,-9 activity in the brain. The increased expression of ICAM-1, GFAP, and the decreased expression of VE-Cadherin, Claudin-5 indicates BBB disruption and vascular inflammation. Moreover, we also found decreased expression of MAP-2, PSD-95, SAP-97, SNAP-25, synaptophysin, and BDNF showing synapse dysfunction in the hippocampus. Furthermore, NaHS and MK801 treatment ameliorates BBB disruption, CBF, and synapse functions in the mice brain. These results demonstrate a neuro-protective effect of H ₂S over Hcy induced cerebrovascular pathology through the NMDA receptor. Our present study clearly signifies the therapeutic ramifications of H ₂S for cerebrovascular diseases such as Alzheimer's disease.

Graphical Abstract