Neuroinflammation appears to be one of the common hallmarks in various age-related degenerative diseases including Alzheimer disease (AD).1 In a new study published in Aging and Mechanisms of Disease, the researchers at the Salk Institute show that tetrahydrocannabinol (THC), the main active chemical ingredient found in cannabis, reduced amyloid beta protein levels in neurons and suppressed the inflammatory response that is triggered by the intracellular accumulation of the protein.2
Aging is the single most important risk factor for neurodegenerative diseases that share pathogenic features such as slow and progressive neuronal death that is concomitant with cognitive dysfunction. The long-standing hypothesis was that aging microglia, the brain’s resident immune cells, acquire a proinflammatory profile and contribute to the generation of a chronic, low-grade inflammatory milieu by releasing cytokines and reactive oxygen species (ROS), which increases vulnerability to neurodegeneration and cognitive decline.3
New findings indicate that intracellular accumulation of amyloid beta within neurons may activate the proinflammatory response, which precedes both amyloid beta plaque formation and concomitant nerve cell death that is observed in age-related neurodegenerative disease such as AD. The researchers show that intraneuronal amyloid beta accumulation triggers the synthesis of immunomodulatory molecules such as interleukin-8 (IL-8), one of the proinflammatory cytokines previously linked to late-onset AD.2,4
Following exposure to THC, which is a potent cannabinoid receptor (CB)-1 agonist, intraneuronal amyloid beta deposits were removed and gene expression of inflammatory cytokines and chemokines was downregulated by blocking the activation of NFkappaB, a protein that plays a key role in regulating the immune response. Neuronal cell death was, however, only partially blocked by THC administration.2
The researchers also reported that proinflammatory cytokine exposure (eg, IL-8, interleukin-1beta, interferon-gamma, or tumor necrosis factor-alpha) potentiates both the intracellular accumulation of amyloid beta and neuronal cell death.
Current therapeutic modalities of neurodegeneration-induced neuronal cell death and concomitant cognitive decline are inadequate, and clinical need is significant. Although mechanism of action is still not completely clarified, cannabinoids appear to reduce intraneuronal amyloid beta load, attenuate amyloid beta-associated neuroinflammation, and diminish cell death. These new data indicate that cannabinoids may have a therapeutically beneficial anti-inflammatory effect to protect human neurons in neurodegenerative diseases such as AD.
1. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140:918-934.
2. Currais A, Quehenberger O, Armando AM, et al. Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids. NPJ Aging Mech Dis. 2016. doi: 10.1038/npjamd.2016.12.
3. von Bernhardi R, Eugenin-von Bernhardi L, Eugenin J. Microglial cell dysregulation in brain aging and neurodegeneration. Front Aging Neurosci. 2015;7:124.
4. Olgiati P, Politis AM, Papadimitriou GN, et al. Genetics of late-onset Alzheimer’s disease: update from the alzgene database and analysis of shared pathways. Int J Alzheimer’s Dis. 2011;832379.