A molecular link between the active component of marijuana and Alzheimer's disease pathology.
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.
Eubanks
Lisa M
LM
Department of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Rogers
Claude J
CJ
Beuscher
Albert E
AE
Koob
George F
GF
Olson
Arthur J
AJ
Dickerson
Tobin J
TJ
Janda
Kim D
KD
D000110:Acetylcholinesterase / Q000737:chemistry; D000544:Alzheimer Disease / Q000473:pathology / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors; D000818:Animals; D002188:Cannabis / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D013759:Dronabinol / Q000737:chemistry / Q000494:pharmacology*; D004593:Electrophorus; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D058225:Plaque, Amyloid / Q000187:drug effects
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D013759:Dronabinol; D000110:Acetylcholinesterase