Abstract
In recent years, Alzheimer's disease (AD) has been recognized as an age-related neurological disorder wherein neurons degenerate and exhibit abnormal structure and function. Aging is the primary factor in the progression of AD from mild to severe cognitive impairment. No effective targeted therapies are presently available, and treatment is limited to symptomatic management. The neuropathologic hallmarks of the disease include the accumulation of amyloid-beta (Aβ) plaques in brain tissues and the aggregation of hyperphosphorylated-tau proteins (tangles) within neurons. Associated hyperactivation of neuroinflammation results in release of inflammatory molecules from neurons, microglia, and astrocytes, which have been linked with neuronal loss and the worsening neurodegeneration. The anti-inflammatory and neuroprotective properties of cannabis-based medicines may offer benefits in delaying the progression of neurodegenerative diseases including AD. This chapter explores the role of cannabinoids in countering neuroinflammation-mediated AD pathology.
TopIntroduction
The cases of dementia have been rising globally in the older population and cause memory impairment with incapability to do daily tasks (Atri, 2019). Many neurological disorders have been associated with memory impairment, and AD is one of them. The cellular and molecular alterations that contribute to AD progression begin years before symptoms appear (Jack Jr et al., 2013). The chances of dementia are approximately 3.9% before the age of 60 years and above. The pervasiveness of Alzheimer’s disease cases in the US, Germany, France, Italy, the UK, Japan, China, and India is supposed to shift from 12.53 million cases in 2012 to 16.72 million cases in 2022. Approximately 6.2 million Americans of 65 age and older have AD-related dementia. AD patients could reach up to 13.8 million by 2060 (Alzheimer’s association 2021). There is an urgent need to find therapeutic targets to protect against AD-associated behavioral and biochemical changes.
The extracellular deposited form of Amyloid β (Aβ) and intracellularly located hyperphosphorylated form of tau protein are the major hallmarks in the disease progression. The aberrant cleavage activity of β-Amyloid Cleaving Enzyme-1 (BACE-1) contributes to cleaving Amyloid precursor protein (APP) at the C-terminus and forms soluble Amyloid precursor protein beta (sAPP β), which further causes dementia and neuronal cell death (Yuksel & Tacal, 2019). The aggregated form of Aβ leads to activating microglia and astrocytes, which produces cytokine storms on the site of damage and attracts other immune cells, causing inflammation and increasing the amount of ROS. The ROS enhances the expression of kinases, including activating Protein kinase C, A, and Extracellular signal-regulated kinase/2(ERK2), which hyper phosphorylates tau protein and destabilizes microtubules and leads to the formation of NFTs and even neuronal cell death(Hooper et al., 2008).
Increasing shreds of evidence have shown that the amyloid cascade is not a single player in the progression of AD. Other events also play a significant role in AD onset, and neuroinflammation is one of them. Inflammation has been involved in repairing tissue injury and protecting cells from infection. The interconnected network of the brain and immune system allows immune cells to work efficiently. Generally, neuroinflammation is a protective mechanism, but its hyperactivation and increased inflammatory mediators cause neuronal cell death. The interconnected networks of activated microglia, astrocytes, and Aβ plaques contribute to neuroinflammation and neuronal cell death, leading to AD progression.
For the last past years, studies have been showing that cannabinoids are a protective warrior to treat AD pathology by targeting Aβ and hyperphosphorylated tau protein(Iuvone et al., 2004a; Ramírez et al., 2005). The combination treatment with three synthetic cannabinoids, including HU-210, WIN55,212-2, and JWH-133, blocked the Aβ-mediated regulation and activation of microglia cells and inhibited TNF- α release (Ramírez et al., 2005). Many studies have shown that it also neutralizes the reactive oxygen species through its antioxidant properties and protects neuronal cells from damage. The CB1 receptor of the endocannabinoid system is aberrantly expressed in the brain, specifically within the hippocampus, basal ganglia, and cerebellum area. The CB1 receptor has an affinity to cannabinoids in the hippocampus and is associated with solid synapse regulation and linked with cognitive functions that are disrupted in AD (Riedel & Davies, 2005). The CB2 is another member, and their low expression in the brainstem, cerebellum, and microglia cells(Ashton et al., 2005; van Sickle et al., 2005). It has the potential to control AD pathology.
Key Terms in this Chapter
Cannabinoid: Cannabinoids are the pharmacologically active compound in the cannabis plant and have antioxidant and neuroprotective properties that protect motor neurons.
Amyloid Beta (Aß): It’s a 36-43 amino acid peptide that is produced by the proteolytic cleavage of a transmembrane protein, amyloid precursor protein (APP) by the action of ß- and ?-secretases. The accumulated form of Aß caused Alzheimer’s disease.
Neurodegenerative Disease: Neurodegenerative diseases are age-dependent neurological dysfunctions in which neurons are progressively damaged in their structure as well as function. Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis (ALS), and Huntington’s disease are neurodegenerative diseases.
Astrocytes: It’s a star-shaped astroglia cell within the brain and spinal cord. They maintained the biochemical function of the Blood Brain Barrier (BBB) and provide nutrients to the nervous system. It also plays a major role in the repair and scarring process of the brain and spinal cord at the time of infections and injuries.
Microglia: It’s a phagocytic macrophage linked with the clearance of damaged neurons and also helps to repair the tissue invaded by pathogens.
G-PCR: It is a seven-transmembrane integral membrane protein that is anchored on the cell membrane. It responds to different types of signaling molecules including light, hormones, neurotransmitters, and lipids.
Alzheimer’s Disease: It’s a neurodegenerative disease wherein cholinergic neurons within an area of hippocampus and cortex regions are degenerated and affected and leading to dysfunction in learning and memory.
Neuroinflammation: Neuroinflammation is a protective mechanism to work against damage, sometimes due to its hyperactivation and production of large amounts of inflammatory molecules that caused detrimental and destructive effects in the neuronal cells within an area of the brain.
CB Receptor: These receptors are mediated by G-protein coupled receptors including CB1 and CB1 and located in the brain regions and have been associated with the psychoactive function of cannabinoids.