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Comparative Study
, 3 (6), 773-7

A Molecular Link Between the Active Component of Marijuana and Alzheimer's Disease Pathology

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Comparative Study

A Molecular Link Between the Active Component of Marijuana and Alzheimer's Disease Pathology

Lisa M Eubanks et al. Mol Pharm.

Abstract

Alzheimer's disease is the leading cause of dementia among the elderly, and with the ever-increasing size of this population, cases of Alzheimer's disease are expected to triple over the next 50 years. Consequently, the development of treatments that slow or halt the disease progression have become imperative to both improve the quality of life for patients and reduce the health care costs attributable to Alzheimer's disease. Here, we demonstrate that the active component of marijuana, Delta9-tetrahydrocannabinol (THC), competitively inhibits the enzyme acetylcholinesterase (AChE) as well as prevents AChE-induced amyloid beta-peptide (Abeta) aggregation, the key pathological marker of Alzheimer's disease. Computational modeling of the THC-AChE interaction revealed that THC binds in the peripheral anionic site of AChE, the critical region involved in amyloidgenesis. Compared to currently approved drugs prescribed for the treatment of Alzheimer's disease, THC is a considerably superior inhibitor of Abeta aggregation, and this study provides a previously unrecognized molecular mechanism through which cannabinoid molecules may directly impact the progression of this debilitating disease.

Figures

Figure 1
Figure 1
Chemical structure of Δ9-tetrahydrocannabinol (THC).
Figure 2
Figure 2
Predicted binding mode of THC (gray) to AChE (orange ribbon). The catalytic triad residues of AChE (green) and water molecules included in the docking calculations (light blue spheres) are shown.
Figure 3
Figure 3
(A) Kinetic analysis of AChE inhibition by 0.0 (●), 6.25 (▲), 12.5 (◆), and 25.0 μM (■) THC. Steady state kinetic analysis was performed using acetylthiocholine (75-300 μM) and Ellman's reagent (340 μM) at 37 °C. (B) Dixon plots of 1/v versus [THC] at different fixed concentrations of propidium iodide: 0 (●), 6.25 (▲), 12.5 (◆), and 25 μM (■).
Figure 4
Figure 4
Inhibition of AChE-induced Aβ aggregation by THC and propidium (* p < 0.05 versus Aβ only; # p < 0.05 versus Aβ + propidium).

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