Aging and the Endocannabinoid System
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medications Klonopin (clonazepam) and Ativan (lorazepam) are used to treat behavior issues associated with Alzheimer’s disease, but have serious risks to the patient.
Role of the Endocannabinoid System in Alzheimer’s Disease
Endocannabinoid dysfunction or deficiency likely plays a role in development and progression of Alzheimer’s disease. One study at UCLA that started in 2013 is looking at the interaction between cannabis use and the APOE4 gene to see if cannabis users have a lower or greater risk of developing Alzheimer’s disease, especially if they carry the Alzheimer’s gene [1]. So far, no studies have shown mutations in endocannabinoid genes lead to Alzheimer’s; however, it is not clear that studies were looking for such a correlation.
Cannabinoid receptors are at high levels in the healthy brain in the hippocampus and decrease with age. One small study found while brains of Alzheimer’s patients had even less CB1 receptors than healthy brains of the same age, the regions of lower CB1 receptors did not correlate with location of amyloid-beta plaques or tangles [2]. CB2 receptor level is actually increased in the brains of Alzheimer’s patients, most likely to combat the neuroinflammation occurring [3,4]. There is evidence that CB1 and CB2 receptors are nitrosylated in Alzheimer’s disease and have defective downstream signaling, resulting in endo-cannabinoid deficiency [3].
Activation of CB2 receptors in the brain can reduce activation of microglia that promote inflammation and excitotoxicity, and promote adult neurogenesis, or the birth of new brain cells [5,6]. CB2 receptor deficiency in a rodent model increases amyloid-beta and plaque formation, indicating the role of CB2 in protecting the brain against the development of Alzheimer’s disease [7]. CBD reduces inflammation and gliosis in a mouse model of Alzheimer’s disease, as well as promotes neurogenesis and neuron survival by increase anandamide in the brain [8-10].
The endocannabinoid system can protect against Alzheimer’s disease outside the traditional cannabinoid receptors. Inhibiting breakdown of endocannabinoid 2-AG by using a MAGL inhibitor causes a reduction in beta-amyloid in a mouse model of Alzheimer’s disease [11]. This reduction in beta-amyloid is not caused by actions of 2-AG at either the CB1 or CB2 receptor, but rather, 2-AG acts through PPARy receptors to inhibit BACE1, the enzyme that breaks amyloid precursor protein (APP) into beta-amyloid [11]. Increasing 2-AG also reduces neuroinflammation and neuro-degeneration and improves spatial memory [12,13].
ALZHEIMER’S DISEASE
Alzheimer’s disease impacts 5.1 million Americans, 66% of which are women. By 2050 there will be 13.8 million Americans living with the disease as we continue to live longer and longer. 1 in 3 seniors dies with Alzheimer’s disease or a similar form of dementia. Risk factors for developing Alzheimer’s disease include old age, a family history, having the ApoE4 gene, having a history of traumatic brain injury, heavy smoking of cigarettes, and maintaining an unhealthy diet.
Alzheimer’s disease, the most common form of dementia, is characterized by progressive loss of memory and cognitive function. There are seven stages of disease progression, from no impairment to moderate decline to very severe decline. Alzheimer’s disease is a deficiency in acetylcholine, a neurotransmitter that modulates memory, decision making and wakefulness. It is also characterized by brain plaques which are clumps of beta-amyloid, a protein found in cell membranes of brain cells. Beta-amyloid plaques cause brain inflammation and block signaling between neurons. Finally, neurofibrillary tangles form when tau protein collapses and cannot transport nutrients throughout the neuron, causing cell death.
Neuro Research
Common treatments of Alzheimer’s disease include cholinesterase inhibitors that increase acetylcholine including Aricept (donepezil), Exelon (rivastigmine), and Razadyne (galantamine), and the NMDA antagoinist Nameda (memantine). Other drugs such as sleep medications Ambien (zolpidem) and Lunesta (eszopiclone) or anti-anxiety
Symptoms of Alzheimer’s disease include:
• memory loss
• vision problems
• believing things that are not true
• irritability and aggression
• mood swings or depression
• inability to multitask
• difficulty planning or solving
problems
• forgetting events, conversations
and appointments
• misplacing items, often in
inappropriate locations
• getting lost in familiar places
like the supermarket
• asking the same questions over
and over again
• forgetting the names of family,
friends, foods and other familiar
things