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Pharmacology of Alzheimer’s Disease

According to the National Institute of Aging, Alzheimer’s disease (AD) is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills and, eventually, the ability to carry out the simplest tasks. It is the 6th leading cause of death in the United States and the most common cause of dementia among older adults. This disease was named after Dr. Alois Alzheimer in 1906, after he studied the brain tissue of a woman who had died of an unusual mental illness. He found abnormal clumps, now better known as amyloid plaques and tangled bundles of fibers or neurofibrillary tangles which are characteristic to the disease.

Pharmacology of Alzheimer’s Disease

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Approximately 5.8 million Americans above the age of 65 have AD, with more than 3 million cases per year. “One in 10 people aged 65 and older (10 percent) has Alzheimer’s Disease, almost two-thirds of individuals with Alzheimer’s are women, older African-Americans are about twice as likely while Hispanics are about one and one-half times as likely to have Alzheimer’s Disease or other dementias as older whites” (Alzheimer’s Association, n.d.). “In most people with the disease—those with the late-onset type—symptoms first appear in their mid-60s. Early-onset Alzheimer’s Disease occurs between a person’s 30s and mid-60s and is very rare” (National Institute of Aging, 2017).

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The most common symptom of AD is facing difficulty in learning new information. Memory problems as such and difficulty remembering old information are typically the first signs of AD. “A decline in other aspects of thinking such as finding the right words, vision/spatial issues, and impaired reasoning or judgment may also signal the very early stages of Alzheimer’s disease” (National Institute of Aging, 2017). Some people with mild cognitive impairment may also develop the disease, but this is not the case for everyone. Due to failing brain cells, people with AD experience serious memory loss, confusion about events, time, and place, disorientation, changes in mood and behavior, and difficulty in speaking, swallowing, and walking. “People with Alzheimer’s have trouble doing everyday things like driving a car, cooking a meal, or paying bills. They may ask the same questions over and over, get lost easily, lose things or put them in odd places, and find even simple things confusing. As the disease progresses, some people become worried, angry, or violent,” (National Institute of Aging, 2017) which makes it a highly debilitating condition.

Even though the pathophysiology of this disease is not entirely understood, there are several hypotheses attempting to explain the underlying neural mechanisms of the disease; namely the cholinergic hypothesis, amyloid hypothesis, and tau hypothesis. The cholinergic hypothesis takes into account the loss of central cholinergic neurons in the brain, which ensues deficiency of the neurotransmitter acetylcholine involved in memory and learning. The amyloid hypothesis takes into account the accumulation of abnormally folded beta-amyloid proteins. Beta-amyloid is a metabolic waste product present in the fluid between brain cells. In AD, beta-amyloid clumps together to form amyloid plaques, which induces neuroinflammation and disrupts communication between neurons. Lastly, the tau hypothesis explores the abnormal aggregation of tau proteins leading to the formation of tangles within nerve cells in the brain. Tau protein in a healthy brain helps to lengthen and support the structure of microtubules. Abnormal aggregation and association of tau in AD compromises the microtubule structure, thereby disrupting the neuron’s transport system.

A lot of research focuses on identifying possible environmental, behavioral, and physiological factors that may impact the prevalence of AD. For instance, an article in the Biomedical Research for Nursing suggests that “environmental and behavioral interventions such as therapeutic touch have the potential to decrease vocalization and pacing, prevalent behaviors, and may mitigate cortisol levels in persons with AD” (Woods & Dimond, 2002). Another study suggests that differences in diet can lead to cognitive impairment associated with spatial memory, learning, and result in a predisposition to develop AD in younger ages. For instance, “diabetes is one of the major risk factors for AD development, a high sugar diet that can lead to the development of diabetes during the first years of life and similarly increase the risk for AD in younger ages” (Rivera, Inestrosa & Bozinovic, 2016). The same study also found that early life social experiences such as growing up in a stressful social environment has “long term effects on behavior and cognitive responses and risk for development of AD in later life”. It is also known that progression of AD “is benefitted by lifestyle strategies such as physical exercise, enriched environments, and nutrition” (Gimenez-Llort, Torres-Lista, & De la Fuente, 2014).

Animal models of the disorder have been used by researchers to further investigate new treatment and pharmacotherapies for the disorder. For instance, transgenic mice that overexpress the human form of amyloid precursor protein and develop deposits of beta-amyloid and behavioral deficits during adulthood have been used to investigate

the capacity of two acetylcholinesterase inhibitors – physostigmine and donepezil to reduce the symptoms of AD such as formation of beta-amyloid plaque formation and memory-related behaviors. “Beginning at 9 months of age, increasing doses of physostigmine (0.03, 0.1, and 0.3 mg/kg), donepezil (0.1, 0.3, and 1.0 mg/kg), or saline were administered over 6 weeks to cohorts of Tg2576-transgenic Tg(+) and Tg2576-transgenic-negative Tg(-) mice. Performance on tests of spatial reversal learning and fear conditioning was evaluated at each drug dose throughout the period of drug administration. After drug administration was completed, the animals were sacrificed and the quantity of plaques were determined” (Dong et al., 2005). The results of this experiment found that “administration of physostigmine and donepezil improved deficits in contextual and cued memory in Tg(+) mice so that their behaviors became more similar to Tg(-) mice. However, administration of physostigmine and donepezil tended to improve cued memory and deficits in spatial learning in both Tg(+) and Tg(-) mice. Physostigmine administration demonstrated more prominent effects in improving contextual memory than donepezil, while donepezil was more effective than physostigmine in improving deficits in the acquisition of the spatial memory paradigm. Administration of neither drug altered the deposition of beta-amyloid plaques” (Dong et al., 2005). Therefore, acetylcholinesterase inhibitors can ameliorate memory deficits in Tg(+) mice but does not necessarily alter the deposition of beta-amyloid plaques.

Currently, there are only two classes of drug treatments which provide only mild symptomatic benefit to individuals with AD. These drug treatments consist of cholinesterase inhibitors (CI) and NMDA receptor antagonists (NRA). Cholinergic neurons in the brain synthesize acetylcholine from Acetyl Coenzyme A and Choline, catalyzed by the enzyme Choline Acetyltransferase (CAT). Acetylcholine is then released and binds to the acetylcholine receptors on the postsynaptic terminal. Two enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) break down acetylcholine into acetate and choline to terminate stimulating signals. According to the cholinergic hypothesis, Alzheimer’s has been linked to a deficiency of acetylcholine in the brain. CI alleviate the symptoms of the disease by inhibiting cholinesterase enzymes AChE and BuChE from breaking down acetylcholine. This makes more acetylcholine available in the brain. Three of the most common cholinesterase inhibitors prescribed are Donepezil (marketed under the brand name Aricept), Rivastigmine (Exelon), and Galantamine (Razadyne). Rivastigmine is known to show significant inhibition of AchE and BuChE. Side effects of these drugs may be mild, causing nausea, vomiting, and diarrhea or serious, causing slow heartbeat, lack of appetite, and substantial weight loss.

On the other hand, NMDA receptors belong to ionotropic glutamate receptors, and they mediate excitatory synaptic transmission in the brain. NRA plays a role in learning and memory. In patients with AD, beta amyloid accumulation causes abnormal rise in extra synaptic glutamate by inhibiting glutamate uptake or triggering glutamate release by glial cells. Binding of glutamate to NMDA receptor causes influx of extracellular calcium ions which control membrane excitability and synaptic transmission. Abnormally elevated levels of glutamate causes overstimulation of NMDA receptors which results in large influx of calcium which causes the cell to eventually rupture and die. NRA called memantine (Namenda) blocks NMDA receptors, limiting abnormal calcium reflux into the neuron. Side effects of memantines include diarrhea, headache, and insomnia.

The drugs which are currently available only provide temporary symptomatic relief, but they do not stop or slow down the underlying neurodegenerative process. As the disease progresses, brain cells die and connections among cells are lost, causing cognitive symptoms to worsen. Current medications cannot stop the damage caused to brain cells, and doctors often prescribe both CI and NRA such as a combination of memantine and donepezil (Namzaric) to patients. Symptoms of AD include behavioral and personality changes such as irritability, anxiety, depression, aggression, anger, agitation, emotional distress, physical or verbal outbursts, restlessness, pacing, shredding paper or tissues, hallucinations, delusions, sleep issues, and sundowning.

Often times, conditions separate from AD may contribute to changes in behavior. “Many people with AD take prescription medications for other health issues. Drug side effects or interactions among drugs can affect behavior. Sometimes, patients are unable to report symptoms of common illnesses. Pain from infections of the urinary tract, ear or sinuses may lead to restlessness or agitation. Discomfort from a full bladder, constipation, or feeling too hot or too cold also may be expressed through behavior.

Uncorrected problems with hearing or vision can also contribute to confusion and frustration and foster a sense of isolation” (Alzheimer’s Association, n.d.). Some medications commonly used to treat behavioral and psychiatric symptoms of AD are antidepressants for low mood and irritability, anxiolytics for anxiety, restlessness, verbally disruptive behavior and resistance, and antipsychotic medications for hallucinations, delusions, aggression, agitation, hostility and uncooperativeness. Medications such as tricyclic antidepressants, benzodiazepines, sleeping pills, and antipsychotics are examples of medications used to treat sleep changes caused by AD.

Current medications only attempt to ameliorate the numerous side effects of the disease. Most experimental drugs have failed to show significant improvement in slowing down the progression of the disease. Thus, new experimental drugs need to be developed to target the root causes of the disease.

According to the amyloid hypothesis, activity of the beta-secretase enzyme at the Amyloid precursor protein (APP) forms insoluble fragments of the monomer amyloid-beta. These monomers bind together to form the plaques which eventually disrupts neuron-to-neuron signalling and leads to neuroinflammation. In a normal brain, the protein Triggering receptor expressed on myeloid cells-2 (TREM2) is an immunomodulatory receptor which binds with ligands to maintain myeloid cell homeostasis, enable phagocytosis, and regulate neuroinflammation by clearing beta-amyloid plaques from the brain. In a brain with AD, this is not triggered as often, hence building up the plaques. One possible treatment for AD could be introducing the endogenous ligand which binds to TREM2 in order to facilitate the signaling pathway and induce phagocytosis by microglia cells to clear beta-amyloid plaques from the brain. Many potential TREM2 ligands have been proposed by a study done by Kober and Brett on TREM2-ligand interactions, which include Damage-Associated Molecular Pattern (DAMP) biomolecules such as anionic bacterial ligands, myeloid and non-myeloid mammalian cells, anionic ligands on mammalian cells, cellular mammalian proteins, and lipoproteins. In other studies , “TREM2 is reported to bind to several putative ligands, including apolipoprotein E (apoE) and apolipoprotein J (apoJ) which are activated by anionic lipids” (Sudom et al., 2018). ApoJ is also known as clusterin (sulfated glycoprotein 2) which is a protein associated with the clearance of cellular debris and apoptosis.

According to the Tau hypothesis, abnormal chemical changes cause the tau from microtubules to detach and stick to other tau molecules forming neurofibrillary tangles. Since the cause of the detachment is unknown, we cannot come up with a treatment to stop it from occurring. However, finding a way to clear these neurofibrillary tangles from the brain could be a promising way to reduce the damaging effects of AD on the brain. Immunotherapy is one way the tangles can be cleared from the brain by intraperitoneally administering antibodies to the brain. According to a study by Albert et al., two murine anti-tau types of antibody Immunoglobulin G (IgG) named antibody A (abA) and B (abB) displayed similar binding profiles against Tau protein. “The murinized abA is a previously-published antibody binding to the amino-terminal domain of tau and abD binds to a central epitope located just before the four microtubules binding domains of tau”. (Albert et al., 2019). However, the same study states that, “ abA has a 7-fold better affinity than abD” for tau protein.

Since the exact cause of AD is unknown and we currently only have a few hypotheses explaining the neural mechanism of the disease, we can only design treatments based off of these mechanisms. Patients with AD can be treated with the two agents identified above, clusterin and IgG with type abA. Clusterin can be administered intravenously and abA can be administered intraperitoneally to the body. Of course, the dosage of these drugs would have to be determined through clinical tests. Clusterin can be marketed with the trade name ‘ClusterX’ to imply putting a fast and effective stop to clusters (amyloid beta plaques in this case). This drug therapy, along with immunotherapy of IgG and aforementioned medications to reduce the symptoms of AD could be used in conjunction to get the best therapeutic relief from the disease.

Even though we can use our current knowledge of AD to develop new drug therapies, of course these experimental drug therapies still have limitations which we need to study further. We also need to study if the findings from animal models of pharmacotherapy are generalizable to human populations consisting of individual differences such as varying age groups or racial and ethnic backgrounds. Since this is a disease which can be treated but not cured, we need to encourage biomedical research focused on how Alzheimer’s affects the brain, so we can eventually uncover a possible cure for it.

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Pharmacology of Alzheimer's Disease
Artscolumbia
Artscolumbia
According to the National Institute of Aging, Alzheimer’s disease (AD) is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills and, eventually, the ability to carry out the simplest tasks. It is the 6th leading cause of death in the United States and the most common cause of dementia among older adults. This disease was named after Dr. Alois Alzheimer in 1906, after he studied the brain tissue of a woman who had died of an unusual mental illness. He found
2021-11-11 08:43:43
Pharmacology of Alzheimer's Disease
$ 13.900 2018-12-31
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