Uncorrected Author Proof
Journal of Alzheimer’s Disease xx (20xx) x–xx
DOI 10.3233/JAD-140093
IOS Press
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The Potential Therapeutic Effects of THC on
Alzheimer’s Disease
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Chuanhai Cao
a,b,∗
, Yaqiong Li
c
, Hui Liu
a,b
, Ge Bai
c
, Jonathan Mayl
b
, Xiaoyang Lin
a,b
,
Kyle Sutherland
d
, Neel Nabar
e
and Jianfeng Cai
c,∗
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4
a
College of Pharmacy, University of South Florida, Tampa FL, USA 5
b
USF-Health Byrd Alzheimer’s Institute, University of South Florida, Tampa FL, USA 6
c
Department of Chemistry, University of South Florida, Tampa FL, USA 7
d
College of Medicine, University of South Florida, Tampa FL, USA 8
e
Thomas Jefferson University, Philadelphia, PA, USA 9
Accepted 29 April 2014
Abstract. The purpose of this study was to investigate the potential therapeutic qualities of
9
-tetrahydrocannabinol (THC)
with respect to slowing or halting the hallmark characteristics of Alzheimer’s disease. N2a-variant amyloid- protein precursor
(APP) cells were incubated with THC and assayed for amyloid- (A) levels at the 6-, 24-, and 48-hour time marks. THC was
also tested for synergy with caffeine, in respect to the reduction of the A level in N2a/APPswe cells. THC was also tested
to determine if multiple treatments were beneficial. The MTT assay was performed to test the toxicity of THC. Thioflavin T
assays and western blots were performed to test the direct anti-A aggregation significance of THC. Lastly, THC was tested
to determine its effects on glycogen synthase kinase-3 (GSK-3) and related signaling pathways. From the results, we have
discovered THC to be effective at lowering A levels in N2a/APPswe cells at extremely low concentrations in a dose-dependent
manner. However, no additive effect was found by combining caffeine and THC together. We did discover that THC directly
interacts with A peptide, thereby inhibiting aggregation. Furthermore, THC was effective at lowering both total GSK-3 levels
and phosphorylated GSK-3 in a dose-dependent manner at low concentrations. At the treatment concentrations, no toxicity was
observed and the CB1 receptor was not significantly upregulated. Additionally, low doses of THC can enhance mitochondria
function and does not inhibit melatonin’s enhancement of mitochondria function. These sets of data strongly suggest that THC
could be a potential therapeutic treatment option for Alzheimer’s disease through multiple functions and pathways.
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Keywords: Alzheimer’s disease, amyloid- peptide, cannabinoid, CB1 receptor, CB2 receptor, delta(9)-tetrahydrocannabinol,
neurodegeneration
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INTRODUCTION 26
In 2011 alone, 15 million family members have pro- 27
vided more than 17.4 billion hours of care to diagnosed 28
Alzheimer’s disease (AD) patients. That care translates 29
into more than $210 billion of AD-related services [1]. 30
This disease translates into an enormous burden on 31
caregivers, as well as the health care system, both med- 32
∗
Correspondence to: Chuanhai Cao, PhD, College of Pharmacy,
University of South Florida, USF-Health Byrd Alzheimer’s Insti-
tute, 4001 E. Fletcher Avenue, Tampa, FL 33613, USA. Tel.: +1
813 3960742; Email: ccao@health.usf.edu and Jianfeng Cai, PhD,
Department of Chemistry, University of South Florida, Tampa, FL
33620, USA. E-mail: jianfengcai@usf.edu.
ically and economically. To date, there have been no 33
effective treatments developed to cure or delay the pro- 34
gression of AD [2, 3]. By 2050, an estimated 11 to 16 35
million Americans will be living with the disease [1, 36
4]. 37
AD pathology can be divided into two cate- 38
gories, familial inherited AD and sporadic AD. The 39
histopathologies of early onset familial AD and late 40
onset sporadic AD are indistinguishable. Both forms of 41
AD are characterized by extracellular amyloid- (A) 42
peptide, and by amyloid plaques and tau-containing 43
neurofibrillary tangles [3]. The misfolded structure of 44
the A peptides generates a characteristic tendency 45
for their aggregation [5]. It has long been believed 46
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