New Insights into the Endocannabinoidome’s Role in Traumatic Brain Injury and Alzheimer’s Disease

Posted on By Stefan Broselid

The human body is a complex system of interconnected networks, and one of the most fascinating yet understudied is the endocannabinoidome (eCBome). This expanded version of the endocannabinoid system plays a crucial role in maintaining balance throughout our physiology. Recent research has shed light on how the eCBome may be involved in the link between traumatic brain injury (TBI) and Alzheimer’s disease (AD), offering new perspectives on these challenging neurological conditions.

Background

The eCBome and Brain Health

The endocannabinoidome encompasses not only the classic endocannabinoid system – with its cannabinoid receptors (CB1 and CB2) and endogenous ligands like anandamide and 2-arachidonoylglycerol (2-AG) – but also a wider network of related lipid mediators, enzymes, and receptors [1]. This system is involved in regulating mood, pain sensation, appetite, and cognitive function, making it a key player in brain health and neurological disorders.

Traumatic brain injury has long been associated with an increased risk of developing Alzheimer’s disease later in life [2]. However, the molecular mechanisms underlying this connection have remained elusive. A recent study published in Acta Neuropathologica Communications has provided new insights into how the eCBome might be involved in this process [3].

Key Findings

eCBome Changes in TBI and AD

The researchers used a mouse model of mild TBI in both wild-type mice and those genetically predisposed to Alzheimer’s disease (APP-SWE mice). They found several intriguing changes in the eCBome:

  1. Increased 2-AG levels: Both the cortex and hippocampus of APP-SWE mice showed higher levels of 2-AG, a key endocannabinoid. This increase was present regardless of whether the mice had experienced TBI.
  2. Altered N-acylethanolamines: The study found changes in levels of various N-acylethanolamines, including a decrease in N-eicosapentaenoylethanolamine (EPEA) in the cortex of injured APP-SWE mice.
  3. Novel brain compounds: For the first time, N-acylserotonins were identified in the brain. These compounds showed different responses to injury in wild-type and APP-SWE mice.
  4. Receptor changes: The study found increased formation of heteromers (combined receptors) between CB1 (cannabinoid) and 5-HT2A (serotonin) receptors in the cortex of injured APP-SWE mice.
*Figure 6 from Guida et al., 2024, republished under Creative Commons License 4.0 (http://creativecommons.org/licenses/by/4.0/). No changes have been made to the figure.

Implications for TBI and Alzheimer’s Disease

These findings suggest that the eCBome plays a complex role in the brain’s response to injury and in the development of Alzheimer’s-like pathology. The increased levels of 2-AG in APP-SWE mice might represent an attempt by the brain to protect itself, as previous research has shown that 2-AG can reduce the production of beta-amyloid, a key player in Alzheimer’s disease [4].

The discovery of N-acylserotonins in the brain opens up new avenues for research. These compounds, which interact with both the endocannabinoid and serotonin systems, could provide new targets for therapeutic interventions in both TBI and early-stage Alzheimer’s disease.

The formation of CB1-5HT2A heteromers in injured APP-SWE mice is particularly intriguing. This receptor interaction has been previously linked to cognitive impairment induced by THC, the main psychoactive component of cannabis [5]. Its presence in this context suggests it might play a role in the cognitive deficits associated with both TBI and AD.

Looking Forward

New Directions in eCBome Research

This study highlights the potential of targeting the eCBome for both preventing and treating neurological disorders. By understanding how this system responds to brain injury and contributes to the development of Alzheimer’s disease, researchers may be able to develop new therapeutic strategies.

For instance, compounds that modulate 2-AG levels or target specific N-acylserotonins could potentially be developed as treatments for TBI or early-stage AD. Additionally, drugs that affect the formation or function of CB1-5HT2A heteromers might help prevent or alleviate cognitive impairments associated with these conditions.

Conclusion

The endocannabinoidome is emerging as a crucial player in brain health and disease. This research not only provides new insights into the molecular links between traumatic brain injury and Alzheimer’s disease but also opens up exciting new possibilities for therapeutic interventions.

As we continue to unravel the complexities of the eCBome, we move closer to developing more effective treatments for these challenging neurological conditions.

For more information on the ECS and its role in health and disease, visit our previous blog posts:

References

  1. Di Marzo V. (2018). New approaches and challenges to targeting the endocannabinoid system. Nature Reviews Drug Discovery, 17(9), 623-639.
  2. Mielke MM, et al. (2022). Traumatic brain injury and risk of Alzheimer’s disease and related dementias in the population. Journal of Alzheimer’s Disease, 88(3), 1049-1059.
  3. Guida F, et al. (2024). Early biomarkers in the presymptomatic phase of cognitive impairment: changes in the endocannabinoidome and serotonergic pathways in Alzheimer’s-prone mice after mTBI. Acta Neuropathologica Communications, 12, 113.
  4. Chen R, et al. (2012). Monoacylglycerol lipase is a therapeutic target for Alzheimer’s disease. Cell Reports, 2(5), 1329-1339.
  5. Viñals X, et al. (2015). Cognitive impairment induced by Delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors. PLoS Biology, 13(7), e1002194.
Scientific Summary