New Glaucoma Research from the United Kingdom: Could a Glaucoma Treatment also Help Prevent Alzheimer's Disease?
by Maureen Duffy
Two recent United Kingdom-based eye research projects have begun to explore potential (but not yet proven) links between retinal disease and beta-amyloid proteins that accumulate in the brains of people with Alzheimer's disease.
The first project, from the University of Southampton, England, investigated the potential role of beta-amyloid protein in the development of macular degeneration.
The second project (explained below), from researchers at University College London (UCL), used mouse models to determine that the drug brimonidine, routinely used to lower glaucoma eye pressure, also reduced the formation of beta-amyloid proteins in the retina, which are linked to Alzheimer's disease.
According to study co-author Francesca Cordeiro, M.D., Ph.D., "The findings of our study could not have come at a more significant and important moment, given the increased prevalence of Alzheimer’s disease. As we live longer, there will be increasing demand for therapies that can help challenge this extremely damaging disease and we believe that our findings can make a major contribution.
Please note that this research does not indicate that macular degeneration or glaucoma can result from Alzheimer's disease, or that one condition can contribute to the development of the other. What the research does indicate, however, is that studying the behavior of beta-amyloid proteins can provide insight into Alzheimer's disease and the retinal damage that accompanies macular degeneration and glaucoma.
From Cell Death & Disease
This new glaucoma research examining the potential role of beta-amyloid protein has been published in the December 2016 edition of Cell Death & Disease, part of the Nature Group of scientific journals that seeks to promote "areas of experimental and internal medicine within its specialties, including cancer, cancer metabolism, immunity, and neuroscience."
The authors are Shereen Nizari, Li Guo, Benjamin M. Davis, Eduardo M. Normando, Joana Galvao, Lisa A. Turner, Mukhtar Bizrah, Mohammad Dehabadi, Kailin Tian, and M. Francesca Cordeiro, from University College London (UCL) Institute of Ophthalmology; and the Western Eye Hospital, Imperial College Healthcare Trust, London, United Kingdom.
What is Beta-Amyloid?
In its most basic form, beta-amyloid (BAY-tuh AM-uh-loyd) is a single protein fragment, snipped from a larger protein found in the fatty membrane surrounding nerve cells. Because it is chemically "sticky," these protein fragments tend to clump or cluster, gradually building into hard, insoluble "plaques" in the brain that are one of the hallmarks of Alzheimer's disease. As they cluster, these beta-amyloid plaques erode synapses, which are the connections between nerve cells that help to conduct nerve impulses. Synapses are essential in encoding, consolidating, storing, and retrieving memories.
Please note, however, that there is much still unknown about beta-amyloid, including its role in Alzheimer's disease, as illustrated by the discouraging results of a recent clinical trial for an experimental drug targeting amyloid buildup. According to the New York Times,
An experimental Alzheimer's drug that had previously appeared to show promise in slowing the deterioration of thinking and memory has failed in a large Eli Lilly clinical trial, dealing a significant disappointment to patients hoping for a treatment that would alleviate their symptoms.
The failure of the drug, solanezumab, underscores the difficulty of treating people who show even mild dementia, and supports the idea that by that time, the damage in their brains may already be too extensive. And because the drug attacked the amyloid plaques that are the hallmark of Alzheimer's, the trial results renew questions about a leading theory of the disease, which contends that it is largely caused by amyloid buildup.
About the Glaucoma/Amyloid Research
Excerpted from Glaucoma drug may have potential to treat Alzheimer's disease, via UCL News:
A drug which is used to treat the common eye disease glaucoma may have potential as a treatment for Alzheimer’s disease, according to scientists at UCL.
In trials on rats, the drug brimonidine, which is routinely used to lower eye pressure in glaucoma patients, has been found to reduce the formation of amyloid proteins in the retina, which are believed to be linked to Alzheimer's.
Amyloid plaques can be seen in the retinas of people with Alzheimer's, so the researchers say the retina can be viewed as an extension of the brain that provides an opportunity to diagnose and track progression of Alzheimer's.
Scientists found that brimonidine reduces [the degeneration of nerve cells] in the retina by cutting the levels of beta-amyloid in the eye. This was achieved by using the drug to stimulate the production of an alternative non-toxic protein which does not kill nerve cells.
The researchers hope that the drug will have a similar effect on the brain, although this was not tested in the current study.
What Is Brimonidine?
Brimonidine (brand names Alphagan and Alphagan-P) is a drug that is used in an eye drop formulation to treat open-angle glaucoma and ocular hypertension. It decreases intraocular [i.e., within the eye] pressure by reducing the production of aqueous humor and increasing the outflow of the aqueous fluid. You can learn more about the full range of treatments for glaucoma at What Are the Different Treatments for Glaucoma? at VisionAware.
What Is Glaucoma?
Glaucoma is a group of eye diseases that can lead to blindness by damaging the optic nerve, which transmits information from the eye to the brain, where it is processed and interpreted. The eye continuously produces a fluid, called the aqueous, that must drain from the eye to maintain healthy eye pressure. Glaucoma is particularly dangerous to your vision because there are usually no noticeable initial symptoms or early warning signs.
The Different Types of Glaucoma
Primary Open Angle Glaucoma
The most common type of glaucoma is Primary Open Angle Glaucoma (POAG). In POAG, the eye's drainage canals become blocked, and the fluid accumulation causes pressure to build within the eye. This pressure can cause damage to the optic nerve, which transmits information from the eye to the brain.
Vision loss is with this type of glaucoma is usually gradual, and often there are no early warning signs. There is a strong genetic predisposition for this type of glaucoma.
Angle Closure Glaucoma
Angle Closure Glaucoma is much less common than POAG in the United States. In this type of glaucoma, the aqueous cannot drain properly because the entrance to the drainage canal is either too narrow or is closed completely. In this case, eye pressure can rise very quickly and can be triggered by pupil dilation.
Symptoms can include sudden eye pain, nausea, headaches, and blurred vision. If you experience these symptoms, you should seek immediate medical treatment.
Normal Tension Glaucoma
In this type of glaucoma, also called low-pressure glaucoma, there is damage to the optic nerve, even though the eye pressure is not elevated excessively. A family history of any type of glaucoma, cardiovascular disease, and Japanese ancestry are a few of the risk factors for this type of glaucoma.
This type of glaucoma is treated much like POAG, but the eye pressure needs to be kept even lower to prevent progression of vision loss.
The typical progression of vision loss from glaucoma
Source: National Eye Institute
National Glaucoma Awareness Month provides a perfect opportunity to learn more about glaucoma, a leading cause of vision loss that affects more than 3 million people in the United States. Glaucoma often is called "the sneak thief of sight" for good reason: Many people are unaware that glaucoma has few symptoms or warning signs in its early stages. Early treatment for glaucoma can usually (but not always) slow the progression of the disease. However, as of yet, there is no cure for glaucoma.
Because glaucoma has no obvious initial symptoms, a comprehensive dilated eye exam is critical to detect early glaucoma changes. People who are over 40 should have a dilated eye examination from an ophthalmologist or optometrist at least every two years. African Americans; people who are over 35 and have a family history of glaucoma; and everyone age 60 or older should schedule a comprehensive eye examination every year.
You can learn more about glaucoma detection and treatment at How Can I Detect Glaucoma if There Are No Initial Symptoms?, What Are the Different Treatments for Glaucoma?, and Tips for Taking Glaucoma (and Other) Eye Drops at VisionAware.
More about the Study from Cell Death & Disease
First, here is a brief explanation of some key terms used in the research:
- Retinal ganglion cells (RGCs): Neurons, or nervous system cells. They are located near the inner surface of the retina and give rise to optic nerve fibers that transmit information from the retina to several regions in the brain.
- Amyloid precursor protein: Plays an essential role in nerve growth and repair. However, later in life, a corrupted form can destroy nerve cells, leading to the loss of thought and memory in Alzheimer's disease.
- Neuroprotective: Protecting nerve cells from damage, degeneration, or impairment of function.
- Neurodegeneration: Degeneration of the nervous system, especially of neurons in the brain.
- In vivo: Processes taking place in a living organism.
- In vitro: Processes or reactions taking place in a test tube, culture dish, or elsewhere outside a living organism.
Excerpted from the study (and simplified for non-scientist readers), with the full article available online:
Glaucoma is a major cause of visual impairment worldwide and is characterized by optic neuropathy [i.e., optic nerve damage] and visual field loss. Retinal ganglion cell death is considered an early hallmark of glaucoma and raised intraocular pressure (IOP) is presently the only modifiable risk factor. As a proportion of glaucoma patients continue to lose vision despite effective IOP control, IOP-independent risk factors are increasingly thought to have a role in glaucoma pathology.
Amyloid beta, the major constituent of senile plaques in Alzheimer's disease, has recently been implicated in glaucoma pathology. Amyloid beta is associated with abnormal processing of amyloid precursor protein.
Using rodent glaucoma models, the pathway of amyloid deposit formation has recently been identified as a target for the development of novel neuroprotective glaucoma therapies. Here, amyloid beta deposits were found to induce retinal ganglion cell death, a finding supported by a study on glaucoma patients reporting reduced amyloid beta concentrations in the vitreous. Amyloid beta may therefore be important in the stress–response to glaucoma neurodegeneration and offers a novel therapeutic target.
Brimonidine, an alpha adrenergic receptor agonist was introduced as an IOP-lowering agent; however, increasing experimental evidence suggests it also has IOP-independent neuroprotective activity.
The present study confirms the neuroprotective actions of alpha adrenergic receptor agonists, using in vivo and in vitro models of retinal neurodegeneration with a novel IOP-independent mechanism of action. This mechanism proposes that a reduction in retinal ganglion cell death is achieved through reduced amyloid beta production, and its amyloid precursor protein.
The applications of alpha adrenergic receptor agonists may therefore not be limited to reducing retinal ganglion cell death in glaucoma, but also to any neurodegenerative process where amyloid beta nervous system damage is involved, such as Alzheimer's disease. This work strongly advocates investigation of the therapeutic potential of alpha adrenergic receptor agonists in these disorders.
For more detailed and patient-centered glaucoma information, see Discovering the Sneak Thief: Diagnosing Glaucoma in VisionAware's Patient's Guide to Living with Glaucoma and El descubrimiento del ladrón silencioso: El diagnóstico de glaucoma in Guía del Paciente: Vivir con Glaucoma.
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