Silencing Genes: A Breakthrough for Alzheimer’s Treatment

Alzheimer’s disease impacts over six million people in the United States, with one in three seniors dying of Alzheimer’s or another form of dementia—amounting to a death rate higher than breast cancer and prostate cancer combined. It is the most common cause of dementia, accounting for 60 to 80 percent of cases. Beginning with mild memory loss in what is referred to as early-onset Alzheimer’s—a variant of the disease which develops before age 65—Alzheimer’s is a progressive disease, with symptoms of dementia gradually worsening in the years following. In its later stages, it leads to an inability to process surroundings and complete daily tasks, mood changes, and increased aggression and anxiety. Its impact on an individual’s life is debilitating in most cases.

Early-onset Alzheimer’s can start as young as a person’s 30s. Though it is rare, it holds significance considering the neurodegeneration and cognitive impairment which occurs in the brain of someone with the disease. The human brain holds about 100 billion nerve cells (neurons) which each play their own roles in basic cognitive functions, such as learning, thinking, and remembering. Neurons, like other cells, need to effectively generate energy, intake nutrients, and dispose of waste in order to operate properly. One important structure which transports nutrients across cells and assists with mitosis—somatic cell division—is the microtubule. Microtubules also serve as part of the structural cytoskeleton for neurons, helping to maintain the cell’s shape. Axons and dendrites inside of the neuron also benefit from the structural support of microtubules. These structures are two of the primary parts of a neuron, mainly helping with a neuron’s communication and signal transmission. Dendrites receive afferent signals, which are responsible for transporting sensory information to the brain. On the other hand, axons carry efferent signals, which are responsible for transporting signals from the brain to the peripheral nervous system. The peripheral nervous system consists of nerves from the brain and spinal cord, which form a communication network between the central nervous system and the rest of the body. On the basis of these efferent signals, axons are responsible for working with dendrites to ensure that the body can initiate and follow through with actions in response to different stimuli, for example touching a hot pan on your stove and quickly pulling away.

In an individual with Alzheimer’s, neurodegeneration begins at the microtubule level. The gene MAPT—microtubule-associated protein tau—has the primary role of providing the instruction for creating the protein tau. Tau is found throughout the nervous system’s and brain’s neurons. As the gene’s name suggests, tau protein is associated with microtubules, particularly the assembly and stabilization of them. In the brain of someone with Alzheimer’s, these proteins are misshapen due to chemical alterations. These genetically mutant forms of tau are associated with many different neurodegenerative diseases in which tau can no longer carry out its normal functions. It begins to organize itself abnormally in insoluble clusters known as neurofibrillary tangles, which begin to accumulate as Alzheimer’s progresses. These tangles prohibit the neuron’s transport system from working effectively, consequently affecting the signal transmission and reception between neurons.

The second hallmark of Alzheimer’s comes from the extracellular plaque deposit of amyloid-beta (Aβ) peptides. Aβ peptides have no known normal function, with mechanisms in the human brain made to degrade the peptide. Recent research has highlighted that Aβ plaques can stick onto the brain, leading to the death of brain neurons. These harmful plaques are formed as a direct consequence of synapse loss. Synapses are the connections between neurons that allow for communication between them, while also mediating cognition and memory. Two main reasons for synapse loss are a neuron’s failure to maintain functioning axons and dendrites, as well as neuron death. This then puts into perspective the connection between mutant tau protein and Aβ plaques. With mutant tau being a prime cause for neuron failure by preventing the maintenance of healthy axons and dendrites, synapse loss is initiated amongst the brain’s neurons. From synapse loss stems the creation of Aβ plaques, which causes neuron death, further enhancing the effects of synapse loss. A feedback loop is then formed in which mutant tau and Aβ enhance each other’s toxicity and work together to drive healthy neurons into a diseased state.

Current FDA-approved Alzheimer’s treatment only focuses on one of these mechanisms:  Aβ plaques. Aducanumab, a newly approved medication for Alzheimer's, is a monoclonal antibody targeted toward removing Aβ. Monoclonal antibodies are synthetically-created molecules that are able to bind to their targets and eliminate them. In the case of aducanumab, these antibodies cross the blood-brain barrier and then bind to the insoluble Aβ plaques in the brain. Aducanumab’s prime selectivity for these abnormal Aβ forms results in the reduction of plaques in the brain. Though Aβ plaques contribute a great deal to the development of Alzheimer’s and its behavioral and cognitive characteristics, evidence has shown that a reduction in tau might actually have more benefits than focusing on Aβ. Preclinical evidence has exemplified that a reduction in tau can prevent Aβ-related deficits, like synapse loss, which is evident from the role that the two play in driving neurons into a diseased state. This evidence has also suggested that tau mediates Aβ’s toxicity in the early development of Alzheimer’s, making tau a disease mechanism worth focusing on. With the motivation of exploring what targeting tau could do for patients with Alzheimer’s, Dr. Catherine Mummery and her team at the University College London Dementia Research Centre put a new drug to the test.

Given the significance of tau in Alzheimer’s development, these scientists sought to inhibit tau’s production, and turned to the MAPT gene. With this goal in mind, the scientists applied gene silencing. Gene silencing is when the expression of a gene is suppressed, thus stopping the gene from performing its ordinary role in protein production. In order to effectively silence the MAPT gene, scientists focused their trial on the antisense oligonucleotide (ASO) drug BIIB080 (MAPT_RX). ASOs are able to bind to RNA—which creates proteins in the body by translating gene instructions—and alter its ability to interpret these signals. The drug MAPT_RX is a type of ASO which focuses on reducing the concentrations of tau produced by the MAPT gene.

The preliminary clinical trial conducted by Dr. Mummery and her team aimed to evaluate the drug’s safety, as well as its interaction with the body. The trial spanned from August 2017 to February 2020, with 46 patients ranging in age from 64 to 67 with mild Alzheimer’s. Participants were given doses of the drug through intrathecal injections—lumbar punctures (LP)—into the nervous system through the spinal canal. Researchers conducted their analysis by looking at the central nervous system, a reliable indicator since MAPT’s expression of tau protein mainly occurs in neurons of the central nervous system. Over 50 percent reductions of total tau levels were reported after 24 weeks in treatment groups that received the highest dose of the drug.

ASOs have seemingly provided a possible alternative for those suffering from Alzheimer’s. With a focus being brought to tau, this leads the way for a treatment which could possibly prevent Alzheimer’s from progressing, or at least slow down its progression in the brain. This is due to the fact that increased abnormal forms of tau can be detected as early as 20 years before symptoms of dementia appear. As Dr. Mummery stated in the University College London’s report of the trial, further research is needed to fully scope how the drug can slow the progression of Alzheimer’s physical symptoms, such as stiff muscles, loss of balance, and weak muscles or fatigue, which are all results of neuronal death.

Regardless, the results exemplified are a huge step toward demonstrating the feasibility of a drug targeting tau, slowing down and possibly reversing Alzheimer’s. Considering the limited amount of FDA-approved Alzheimer’s medications out there, Dr. Mummery has provided a pathway for another new medication—one that could be far more preventative by targeting a disease mechanism not touched on by currently approved treatments.