Monday, May 11, 2015

Cannabis-Based Medicine As Potential Therapy For Alzheimer's Disease

Alzheimer is an age-dependent neurodegenerative process distinct from normal aging and characterized morphologically by the presence of senile plaques, mainly composed of different species of fibrillar β-amyloid (Aβ) produced by the cleavage of the Aβ precursor protein (APP) due to ß- and γ-secretases, and by the presence of neurofibrillary tangles, mostly composed of various isoforms of hyper-phosphorylated and nitrated tau protein. One tendency of opinion proposes that Aβ triggers plaque formation, tau hyper-phosphorylation, and disease progression. This may happens in a percentage of familial Alzheimer’s disease (AD) cases linked to mutations in genes encoding APP, and presenilin 1 and presenilin 2 which are enzymes involved in the cleavage of APP, or in Down syndrome. However, tau hyper-phosphorylation precedes Aβ deposition in many cerebral regions in sporadic cases of AD.

Recent studies have shown that Aβ acts as a seed of new Aβ production and deposition under appropriate conditions and that abnormal tau promotes the production and deposition of hyper-phosphorylated tau under determinate experimental conditions. Therefore, Aβ and hyper-phosphorylated tau promote the progression of the pathological process in an exponential way once these abnormal proteins are accumulated in the brain.

During the last few years, targeting the endogenous cannabinoid system (ECS) has emerged as a potential therapeutic approach to treat Alzheimer in such first stages. The endocannabinoid system is composed by a number of cannabinoid receptors, including the well-characterized central and peripheral neurons (CB1) and immune cells (CB2) receptors, with their endogenous ligands and the enzymes related to the synthesis and degradation of these endocannabinoid compounds. Several findings indicate that the activation of both CB1 and CB2 receptors by natural or synthetic agonists, at non-psychoactive doses, have beneficial effects in Alzheimer experimental models by reducing the harmful ß-amyloid peptide action and tau phosphorylation, as well as by promoting the brain’s intrinsic repair mechanisms. Endocannabinoid signaling has been demonstrated to modulate the main pathological processes occurring during the silent period of the neurodegenerative process, including protein misfolding, neuroinflammation, excitotoxicity, mitochondrial dysfunction, and oxidative stress.

Here are summarized two studies where Cannabis has successfully stopped Aβ production.

Study 1 [1]

Since the characterization of the Cannabis sativa-produced cannabinoid, Delta-9-tetrahydrocannabinol (THC), in the 1960's, this natural product has been widely explored as an anti-emetic, anti-convulsive, anti-inflammatory, and analgesic. In contexts to Alzheimer, efficacy results from THC binding to the family of cannabinoid receptors found primarily on central and peripheral neurons (CB1) or immune cells (CB2). The active component of marijuana, Delta-9-tetrahydrocannabinol (THC), competitively inhibits the enzyme acetylcholinesterase (AChE) as well as prevents AChE-induced amyloid beta-peptide (Aβ) 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 Aβ aggregation, and study provides a previously unrecognized molecular mechanism through which cannabinoid molecules may directly impact the progression of this debilitating disease.

Study 2 [2]

This study demonstrated that delta-9-tetrahydrocannabinol (THC) or cannabidiol (CBD) botanical extracts, as well as the combination of both natural cannabinoids, which are the components of an already approved cannabis-based medicine, preserved memory in AβPP/PS1 transgenic mice when chronically administered during the early symptomatic stage. Moreover, THC + CBD reduced learning impairment in AβPP/PS1 mice. A significant decrease in soluble Aβ42 peptide levels and a change in plaques composition were also observed in THC + CBD-treated AβPP/PS1 mice, suggesting a cannabinoid-induced reduction in the harmful effect of the most toxic form of the Aβ peptide. Among the mechanisms related with these positive cognitive effects, the anti-inflammatory properties of cannabinoids may also play a relevant role. Researchers observed reduced astrogliosis, microgliosis, and inflammatory-related molecules in treated AβPP/PS1 mice, which were more marked after treatment with THC + CBD than with either THC or CBD. Moreover, other cannabinoid-induced effects were uncovered by a genome-wide gene expression study. Researchers also identified the redox protein thioredoxin 2 and the signaling protein Wnt16 as significant substrates for the THC + CBD-induced effects in our AD model. The present findings show that the combination of THC and CBD exhibits a better therapeutic profile than each cannabis component alone and support the consideration of a cannabis-based medicine as potential therapy against AD.

These studies have demonstrated the ability of cannabinoids to provide neuroprotection against β-amyloid peptide (Aβ) toxicity. Yet, it is important to note that in these reports, cannabinoids serve as signaling molecules which regulate downstream events implicated in Alzheimer's disease pathology and are not directly implicated as effecting Aβ at a molecular level.

1. Eubanks, L. M.; et. al. A molecular link between the active component of marijuana and Alzheimer's disease pathology. Mol Pharm 2006, 3(6), 773-777.
2. Ester, A.; et. al. Cannabis-Based Medicine Reduces Multiple Pathological Processes in AßPP/PS1 Mice. Journal of Alzheimer's Disease 2015, 43(3). DOI: 10.3233/JAD-141014