If you’ve done any research on the neurochemistry of Alzheimer’s Disease (AD), you’ve probably run into a few of the same molecular players like β-amyloid plaques and tau tangles that are present in the disorder. However, despite promising strides in AD research, fundamental questions about the disease still remain unclear, like why these plaques and tangles form, causing AD to happen to certain people and not others, or how best to treat the disease. Recently, a new player in the development of AD has been discovered: the endocannabinoid system. Let’s take a look at what this system is and how preliminary research has implicated its role in AD.
The Endocannabinoid System
The endocannabinoid system (ECS) involves several receptors and ligands (molecules that bind to receptors) in the brain. The CB1 and CB2 receptors are the most prevalent in this system. Both are G-protein coupled receptors (GPCRs), meaning that when the ligand binds, G-proteins associated with the receptors are activated. There are two categories of ligands for these receptors: endogenous endocannabinoids (those that are naturally produced in the brain) and exogenous cannabinoids (external ones that have been ingested, like cannabis). We will be focusing on the endogenous system for this post. The two main endogenous ligands in the ECS are the molecules AEA and 2-AG.
The ECS has a unique modulatory function in the brain because, once activated, it affects the presynaptic neuron. The synapse is the space between neurons (brain cells). Typically, signals are released from presynaptic neurons in the form of neurotransmitters that cross the synapse and serve as ligands for receptors on the postsynaptic neuron. However, the endocannabinoid system signals in the opposite direction in a phenomenon known as retrograde signaling. Activated CB1 and CB2 receptors cause a signaling cascade that releases neurotransmitter from the postsynaptic neuron that travels back to the presynaptic neuron. These signals then modulate the presynaptic neuron’s signaling, which allows the ECS to have broad effects on all signaling done by the presynaptic neuron.
Endocannabinoid signaling helps mediate synaptic plasticity, the ability of a synapse to change in response to signaling activity, which is an important process in learning and memory. The ECS is also important in pain perception, mood regulation, as well as in protection from neurodegeneration and in reducing inflammation in the brain.
Role of ECS in Alzheimer’s Disease
Because the endocannabinoid system assists with memory, reduction of inflammation, and protection from neurodegeneration, it makes sense that dysregulation of the system could play a role in Alzheimer’s Disease. Evidence also supports a role of the system: levels of key molecules are off in AD brains and CB1 and CB2 receptors are correlated with tau tangles and other hallmarks of AD.
Unfortunately, because much about AD remains unknown and researchers still lack a holistic animal model (laboratory animals modified to simulate a disorder; for example, mice whose genome has been edited to cause an autism-like state) for the disorder, few conclusions have been reached about the role of the ECS. Let’s take a look at cursory research that has been done.
- The role of the ECS in AD seems to be similar its role in other neurodegenerative diseases about which more is known, like MS. In these disorders, the role of the endogenous system counteracts the “neurochemical and inflammatory consequences of β-amyloid-induced tau protein hyperactivity”. This means that the ECS protects the brain from negative effects of tau tangles in the brain that lead to development of AD.
- As mentioned above, different levels of key molecules in the ECS have been found in AD brains.
- In AD, there is an elevated number of CB2 receptors in the hippocampus. This is correlated with amyloid plaque, tau tangle levels, and levels of activated microglia (other brain cells that act on neurons).
- There is reduced methylation (addition of meythl groups that prevent a gene from being transcribed and expressed) at the FAAH gene locus in AD. This leads to reduced levels of AEA in temporal and mid-frontal cortex in AD brains, an important ligand in the ECS.
- 2-AG. the other major endogenous endocannabinoid ligand, exists at a potentially elevated level in AD.
Since research is still in its preliminary stages, a clear picture of the role of the ECS in AD remains evasive. Research is contradictory about points as basic as whether ECS signaling is overactive or underactive in AD brains. However, the ECS remains a promising route for future AD research, and CB receptor agonists like exogenous cannabinoids such as CBD have been proposed as potential treatments for AD.
