NDLI: Hydrogen Sulfide Ameliorates Homocysteine-Induced Alzheimer’s Disease-Like Pathology, Blood–Brain Barrier Disruption, and Synaptic Disorder

Content Provider	Springer Nature Link
Author	Kamat, Pradip K. Kyles, Philip Kalani, Anuradha Tyagi, Neetu
Copyright Year	2015
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$_{2}$S), which is a synaptic modulator, as well as a neuro-protective agent. However, the role of hydrogen sulfide, as well as N-methyl-d-aspartate receptor (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$_{2}$S 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 cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) in the brain along with increased expression of NMDA-R (NR1) and synaptosomal Ca$^{2+}$ indicating excitotoxicity. Additionally, we found that Hcy treatment increased protein and mRNA expression of intracellular adhesion molecule 1 (ICAM-1), matrix metalloproteinase (MMP)-2, and MMP-9 and also increased MMP-2 and MMP-9 activity in the brain. The increased expression of ICAM-1, glial fibrillary acidic protein (GFAP), and the decreased expression of vascular endothelial (VE)-cadherin and claudin-5 indicates BBB disruption and vascular inflammation. Moreover, we also found decreased expression of microtubule-associated protein 2 (MAP-2), postsynaptic density protein 95 (PSD-95), synapse-associated protein 97 (SAP-97), synaptosomal-associated protein 25 (SNAP-25), synaptophysin, and brain-derived neurotrophic factor (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$_{2}$S over Hcy-induced cerebrovascular pathology through the NMDA receptor. Our present study clearly signifies the therapeutic ramifications of H$_{2}$S for cerebrovascular diseases such as Alzheimer’s disease. Graphical Abstract ᅟ
Starting Page	2451
Ending Page	2467
Page Count	17
File Format	PDF
ISSN	08937648
Journal	Molecular Neurobiology
Volume Number	53
Issue Number	4
e-ISSN	15591182
Language	English
Publisher	Springer US
Publisher Date	2015-05-28
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Homocysteine Blood–brain barrier dysfunction Cerebrovascular pathology Alzheimer’s disease Dementia Neurosciences Neurobiology Cell Biology Neurology
Content Type	Text
Resource Type	Article
Subject	Neurology Cellular and Molecular Neuroscience

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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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