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New Types of Drug Therapy For the Treatment of Alzheimer's Disease

Updated on November 4, 2016
In the Alzheimer's brain, secretase enzymes (scissors) cleave amyloid precursor protein (blue) to form beta-amyloid fragments (yellow). These fragments proceed through several stages to produce the harmful plaques of Alzheimer's disease.
In the Alzheimer's brain, secretase enzymes (scissors) cleave amyloid precursor protein (blue) to form beta-amyloid fragments (yellow). These fragments proceed through several stages to produce the harmful plaques of Alzheimer's disease. | Source

How Does Beta-Amyoid Plaque Form in the Brain of an Alzheimer's Disease Patient?

Amyloid Precursor Protein (APP) is a large protein found in the brain. Writing in the September 2010 issue of the journal "Cell," researchers reported that they believe APP functions as an iron oxidase. This means that it converts iron from its unsafe oxidative form to a safe reduced form. Two enzymes in the brain, gamma- and beta-secretase, act on APP and cleave it to smaller fragments called A-beta peptides. One of these fragments, a 42-amino acid peptide referred to as A-beta 42, is the primary component of the beta-amyloid plaque thought to cause the nerve cell damage characteristic of Alzheimer's disease. The plaque forms in stages. First, the A-beta 42 gathers into clusters called oligomers, and then the oligomers assemble into chains referred to as fibrils. The fibrils form mats called beta-sheets which clump together to form the sticky plaques. Scientists believe that these plaques disable communication between nerve cells, and this disabling invokes an immune response that ultimately results in the destruction of the nerve cells.

Neurotransmitters carry nerve signals across the synapic gap between the axon of the sending nerve cell and the dendrite of the receiving cell.
Neurotransmitters carry nerve signals across the synapic gap between the axon of the sending nerve cell and the dendrite of the receiving cell. | Source
Because they have a protein structure, monoclonal antibodies like bapineuzumab need to be administered intravenously.
Because they have a protein structure, monoclonal antibodies like bapineuzumab need to be administered intravenously. | Source

New Drug Therapies That Target Beta-Amyloid Plaque

Neurotransmitters are chemical agents that facilitate the transmission of signals from one nerve cell to another. Currently, there are four prescription medications marketed for Alzheimer's disease, and all of them affect brain levels of neurotransmitters associated with learning and memory.Three of these medications focus on the neurotransmitter acetylcholine, and the fourth targets glutamate. The effectiveness of all of these medications is limited to temporarily slowing the progression of Alzheimer's disease. Clearly, there is an urgent need for better drugs that can reverse the course of the disease.

Intensive research efforts have shifted the focus of Alzheimer's drug therapy from modulating neurotransmitters to attempts to clear away the harmful plaques that destroy nerve cells in the brain. This research has led to protein-based drugs called biologics that have progressed to various stages of clinical evaluation:

BAPINEUZUMAB--This is a monoclonal antibody intended to treat mild to moderate cases of Alzheimer's disease, and it is given by i.v. infusion. It works by binding specifically to accumulated plaque in the brain and then clearing it away. This method of administering an antibody is termed a passive immunotherapy approach. It is distinguished from active immunotherapy or vaccination in which the immune system produces antibodies in response to an administered vaccine. Phase II clinical trials on 234 patients were completed in 2008. Results of these trials indicated that patients receiving bapineuzumab who were not carriers of a specific gene that increases the risk of Alzheimer's performed better on cognitive and functional tests than patients on placebo. Although most side effects were mild and short lived, there were 12 cases of vasogenic edema seen at the highest dose level. This type of edema involves the leaking of fluids and proteins from the circulatory system into the brain. All cases were resolved over time after therapy was discontinued, and bapineuzumab progressed to phase III clinical trials.

GANTENERUMAB--Researchers publishing online on October 10, 2011, in the journal "Archives of Neurology," describe a clinical trial with the anti beta-amyloid monoclonal antibody gantenerumab. This is another passive immunotherapy agent that is given by i.v. infusion. In a clinical study of 16 Alzheimer's patients, this agent reduced brain levels of amyloid plaque by 15.6 to 35.7% depending on the dose given. Some instances of vasogenic edema were noted, and these were resolved when the drug was terminated. A phase II study is underway to determine if this reduction in amyloid plaque levels is accompanied by an improvement in cognitive ability.




Gamma-Secretase Modulators, Another Novel Approach to Alzheimer's Therapy

TARENFLURBIL--Gamma-secretase, one of the enzymes that cleaves amyloid precursor protein, has been another target for new Alzheimer's treatments. The action of gamma-secretase on APP produces several protein fragments, but A-beta 42 is the fragment responsible to the formation of amyloid plaque. According to Dr. Todd Golde of the Department of Neuroscience at the Mayo Clinic in Jacksonville, Florida, the idea behind gamma-secretase modulators is that if you can modify the activity of the secretase enzyme, you may be able to reduce the amount of A-beta 42 formed when APP is cleaved. If you can make the enzyme produce mostly fragments shorter than A-beta 42, you can significantly limit the amount of plaque in the brain. Tarenflurbil is one example of a gamma-secretase modulator. This drug is a type of organic compound called a biphenyl, and, unlike the biologics, it has the small-molecule structure of a conventional drug. Clinical studies on tarenflurbil have produced mixed signals about the usefulness of this theapeutic approach to Alzheimer's. In a phase II study, the drug provided some benefits to patients with mild Alzheimer's disease. The results of a phase III study were published in the December 16, 2009, issue of the Journal of the American Medical Association. In this report, Dr. Robert Green of Boston University School of Medicine revealed that tarenflurbil had no significant effect on the cognitive ability or on the ability to carry out daily activities of patients with mild Alzheimer's disease.

Disclaimer

This hub has been written for the sole purpose of providing information to the reader. It is not intended to be a source of any kind of medical advice or instruction, and it should not be used in the diagnosis of any illness, disease or condition. You should consult your doctor if you have questions about a specific medical problem.

New Drugs for Alzheimer's Disease

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