SAC (S-allyl-L-cysteine) as a novel therapeutic agent for Alzheimer’s disease (AD) based on studies from neuronal cultures and APP-Transgenic model for AD

Debomoy K. Lahiri
Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA

Abstract:

Background: AD is characterized by amyloid β-peptide (Aβ) plaques and neurofibrillary tangles. Aβ produces reactive oxygen species (ROS) causing neuroinflammation and neuronal damage. Anticholinesterase drugs are predominantly used for AD but they fail to cure AD. Thus, alternative medications should be developed. From ancient times, garlic (Allium sativum) is used to treat diabetes and cardiovascular disorders. In AD models, we successfully tested a unique preparation, “Aged Garlic Extract” (AGE). AGE contains DAD (Diallyl disulfide) and SAC. Herein, we demonstrate a novel property of SAC in neuroprotection, neuropreservation and synaptic integrity in neuronal cultures and in vivo pertinent to the neurodegenerative disorder AD.

Methods:  For neuroprotection, differentiated neuronal PC12 cells were treated with hyderogen peroxide as the source of ROS and then with different doses of SAC. Western immunoblotiing and choline acetyltransferase (ChAT) assays were performed with cell lysates. Cells were also fixed with  4% paraformaldehyde for morphology analyses by ICC. For neurorescue experiments, neuronally differentiated cells were pre-treated with SAC alone for 48 hours and thereafter, post-treated with ROS alone for 24 hours. Cells were likewise harvested and fixed. Further, APP- transgenic (Tg2576) mice were fed with special diet containing either SAC or isocaloric control diet for 4 months. Animals were sacrificed and the brain was dissected, homogenized, and brain homogenates were subjected to Western immunoblotting and ELISA.

Results:  We observed significant neuroprotective and neurorescue properties of SAC against ROS- mediated insults to neuronal cells. Indeed, SAC preserved pre-synaptic proteins, such as synaptophysin and SNAP-25, in Alzheimer’s Tg mice and ROS-insulted neuronal cells. Notably, AGE  increased levels of ChAT activity in ROS-challenged cells. Interestingly, SAC treatment increased levels of the important choline transporter (VAChT) in APP-Tg mice. Further, potent antioxidant and Aβ lowering properties have also been observed with SAC.  

Conclusion: SAC treatment protects neurons from ROS-mediated oxidative stress and preserves pre-synaptic proteins. SAC treatment reverses ROS-mediated decline in cholinergic function of neuronal cells by increasing neuronal ChAT activity. Synaptic damage from excessive Aβ deposition in APP-Tg mice brain was also prevented by oral SAC treatment. Thus, the pleiotropic effects of SAC can be used as a potential therapeutic agent in treating AD. These findings warrant evaluation of SAC’s clinical potency in larger clinical settings.