Alzheimer’s disease has become incredibly prevalent within the media in the past decade. A neurodegenerative disease afflicting nearly five and a half million people in the United States alone, Alzheimer’s is the sixth leading cause of death in the United States, and the only top 10 cause of death that is currently untreatable.
Alzheimer’s is a form of dementia that worsens over time, and though generally thought to only affect memory (memory loss is one of the first symptoms) it also affects perception and cognitive skills. The disease is caused by the destruction of neuronal pathways within the brain. Because the brain does not form new neuron connections, the elimination of connections is permanent and causes problems with cognitive functioning. The process that leads to the degradation of neuronal pathways is simple. Insoluble protein aggregates, composed of a protein fragment labeled as beta amyloid, form in the brain. These protein aggregates, also known as “plaques,” are then attacked by the brain’s defense system, a type of white blood cell called microglia that exists solely within the brain. The microglia’s normal duty is to act as a clean-up crew for the brain, releasing chemicals known as cytokines and neurotoxins to destroy damaged neurons. The amyloid beta plaques are then attacked by the microglia, which view the plaques as damaged cells. The microglia release their cell-killing chemicals and destroy the normal, functioning cells around the plaque. Losing neurons causes the brain to function at lower levels, leading to the symptoms associated with Alzheimer’s disease.1
Because Alzheimer’s has become so prevalent and widespread, a large part of the scientific consciousness has been devoted to creating drugs that will at first treat the disease and eventually cure it altogether. There are several approaches being employed by researches in creating these medicines to stop Alzheimer’s.
The most traditional approach to eliminating Alzheimer’s disease is to focus on clearing beta amyloid plaques from the brain. At Case Western Reserve, researcher Gary Landreth discovered that the brain’s main cholesterol carrier Apoloipoprotein E (ApoE) expedited the removal of amyloid from the brain. He tested the effect of a successful cancer drug, Bexarotene, on the expression of ApoE. Bexarotene acts by stimulating receptors controlling the levels of ApoE produced. The elevation of brain ApoE levels, in turn, speeds the clearance of amyloid beta from the brain. The researchers were struck by the speed with which bexarotene improved memory deficits and behavior.2
The second approach, being applied by MIT neuroscientists, is to correct the overabundance of regulatory molecules known as histone deacetylases (HDACs). When HDACs alter a histone through a process called deacetylation, chromatin (strands of DNA wrapped around the histone) becomes more tightly packaged, making genes in that region less likely to be expressed. In mice showing symptoms of Alzheimer’s, a certain HDAC – HDAC2 – was overabundant in the hippocampus, where it clung to genes involved in synaptic plasticity. Synaptic plasticity is the brain’s ability to strengthen and weaken connections between neurons in response to new information, which is critical to forming memories.3 Beta amyloid protein aggregates were also shown to increase production of HDAC2. This interference with the creation of memories by HDAC2 may show why clinical trials aimed at beta amyloid have only been marginally successful – clearing the amyloid plaques is not sufficient to return to normal activity within the brain.
One hypothesis that has recently emerged is that Alzheimer’s is very closely related to diabetes, and is really “type-3” diabetes. Research has shown that brain-insulin and receptors related to it are lower in those afflicted with Alzheimer’s. Brain insulin signaling, another process needed for creation of memories, is significantly less active because a toxic protein, derived from amyloid beta, renders neurons insulin resistant by removing the neuron’s receptors for insulin. This discovery may allow diabetes drugs to cross over into the realm of Alzheimer’s. For example, a drug called Liraglutide has been shown to reduce amyloid production and protect neurons against nerve cell damage caused by amyloids.4 The aforementioned toxic protein, known as ADDL (Amyloid-beta derived diffusible ligand), prevents insulin receptors from accumulating at synapses where they are needed and consequentially prevents insulin from binding at that receptor, a sequence necessary for formation of memories. ADDLs build up at the onset of Alzheimer’s disease and block memory function, though clinical data suggests that this process is reversible. Researchers discovered the toxic protein causes a rapid and significant loss of insulin receptors from the surface of neurons specifically on dendrites to which ADDLs are bound. ADDL binding clearly damages the trafficking of the insulin receptors, preventing them from getting to the synapses. The researchers measured the neuronal response to insulin and found that it was greatly inhibited by ADDLs.5
In addition, there is miscellaneous research being done outside of the main areas related to Alzheimer’s. One paper published in 2006 states that the active component of marijuana, THC (Delta9-tetrahydrocannabinol) competitively inhibits the enzyme acetylcholinesterase (AChE) and prevents AChE-induced amyloid beta-peptide aggregation, the key pathological marker of Alzheimer’s disease.5 The paper claims that THC was more effective in treating Alzheimer’s than any of the other approved drugs at the time of publishing. Researchers have also found correlations between Alzheimer’s and the cold sores developed from herpes. They found that the virus causing herpes was located specifically in amyloid beta plaques. 90% of plaques in Alzheimer’s disease sufferers’ brains contain Herpes-Simplex Virus 1 DNA, and most of the viral DNA is located within amyloid plaques. It was previously shown that HSV1 infection of nerve-type cells induces deposition of beta amyloid. Together, these findings strongly implicate HSV1 as a major factor in the formation of amyloid deposits and plaques, abnormalities thought by many in the field to be major contributors to Alzheimer’s disease.6
Affecting over one percent of people worldwide, Alzheimer’s is the most common form of dementia. Currently, there is no cure for Alzheimer’s, and available medicine only aids the sufferer with their symptoms. Because of this, preventing the onset of the disease and eliminating the factors that cause it is being heavily pursued by major research universities, as it would be a major scientific feat. Targeting amyloid beta plaques seems to be the most promising way of preventing Alzheimer’s, and a large amount of literature is devoted to experiments in this area.
- Jasmin, Luc, ed. “Alzheimer’s Disease.” PubMed Health. Accessed November 7, 2012.
- Case Western Reserve. “FDA-approved Drug Rapidly Clears Amyloid from the Brain, Reverses Alzheimer’s Symptoms in Mice.” Medical Xpress. Last modified February 9, 2012.
- Trafton, Anne. “Reversing Alzheimer’s Gene ‘Blockade’ Can Restore Memory, Other Cognitive Functions.” ScienceDaily. Last modified February 29, 2012.
- Edison, Paul. “Testing the Effect of the Diabetes Drug Liraglutide in Alzheimer’s Disease.” Alzheimer’s Society. Accessed November 7, 2012.
- Northwestern University. “Discovery Supports Theory of Alzheimer’s Disease as Form of Diabetes.” Phys Org. Last modified September 26, 2007.
- University of Manchester. “Cold Sore Virus Linked To Alzheimer’s Disease: New Treatment, Or Even Vaccine Possible.” ScienceDaily. Last modified December 7, 2008.
- Image credit (Creative Commons): Hampshire, Stephen. Unnamed image. Flickr. Taken January 26, 2009.
Ian is a first-year student at the University of Chicago majoring in biochemistry. He did research on Alzheimer’s disease as a senior year in high school, and decided to continue to expand his knowledge of the ailment. After college he wants to attend graduate school and eventually perform his own research on drug discovery. Follow The Triple Helix Online on Twitter and join us on Facebook.