The saying goes, “Out of sight, out of mind.” And recent studies by UCSB researchers suggest there may be something to it.

Scientists at UCSB’s Center for the Study of Macular Degeneration (CSMD) have discovered strong experimental evidence that two common age-related ailments, Alzheimer’s disease and macular degeneration, may be related.

“It looks like the two diseases may have a common cause,” CSMD Associate Director Lincoln Johnson said. “But they’re happening in two different organs and with very different effects.”

Out of Sight

Age-related macular degeneration, or AMD, is the leading cause of adult blindness. One out of every 10 people over the age of 60 will lose all or part of their vision to this disease. Until recently, most research has examined the symptoms of AMD, rather than the root cause.

Seven years ago, Don Anderson and Lincoln Johnson founded CSMD in an attempt to fill this void. Along with other researchers at the center, they have developed a unique model of the disease.

A layer of cells called photoreceptors lie at the back of the human eye. This layer of photoreceptor cells forms the screen onto which images of the world are projected by the eye’s lens. Photoreceptor cells tell the brain about the image they are receiving by passing information along the optic nerve. This task requires an enormous amount of energy – so much, in fact, that photoreceptor cells need help to survive.

They get this help from a second layer of cells, called the retinal pigment epithelium (RPE), which lies behind the photoreceptor cells. RPE cells are specialized neurons that serve as nurse cells, providing nourishment for the photoreceptor cells. The RPE cells sit on top of a thin membrane called Bruch’s membrane, which separates them from blood vessels below. The RPE cells draw nutrients from the blood through this membrane.

The CSMD model of macular degeneration holds that AMD begins when, for some reason, a few RPE cells begin to die. The body responds by mounting an immune reaction, similar to the way it responds to a splinter or a cut. The immune reaction consists of a complement response and an inflammatory response.

The complement response is the reaction of a series of proteins to the distressed site. Each set of proteins activates the next, progressively attaching themselves to damaged cells so white blood cells can locate and destroy them, initiating the inflammatory response and helping to lyse (burst) the damaged cells. The complement response can also kill healthy cells at the same time it eliminates damaged cells – a phenomenon known as “bystander lysis.”

The inflammatory response is brought on by the complement response. In the inflammatory response, damaged cells release small molecules called histamines, which make their way into nearby blood vessels. The vessels expand and begin to leak, allowing white blood cells to make their way into the tissue in response to the call of the complement proteins. The white blood cells then destroy the damaged cells, which stop releasing histamines and bring an end to the immune reaction.

In AMD, the immune reaction leaves behind chemical residues called plaques. These plaques interfere with the function of surrounding RPE cells, sending them into distress. So a cycle begins in which RPE cells die, causing the body to mount an immune response. The immune response causes the death of surrounding cells, which initiate another immune response on the part of the body. And the cycle continues.

Plaques eventually build up to form larger structures, known as drusen, beneath the RPE layer. The drusen push the RPE cells up away from their resting places on Bruch’s membrane, depriving them of the nutrients they need to survive. Without the help of the nurse cells in the retinal pigmented epithelium, photoreceptor cells begin to die off. When the photoreceptor cells die in the region of the eye near the optic nerve known as the macula, a blind spot develops in the affected person’s vision.

As the disease progresses, the barrier between drusen and the rest of the retina may break down. Blood vessels sometimes grow into the remaining space. These vessels tend to bleed, causing what is known as the “wet” form of macular degeneration. While the dry form of AMD may take years to progress, the wet form can lead to total loss of vision in less than a week.

CSMD researchers have been studying the molecular composition of drusen for several years to figure out how their presence causes RPE cell death. Now they have found that one of the key components of drusen is a protein commonly associated with Alzheimer’s disease, amyloid beta.

Out of Mind

Alzheimer’s disease is the result of a cyclical immune reaction similar to that found in AMD. In Alzheimer’s, the plaques and progressive cell death affect neurons in the brain, rather than RPE cells in the eye. Alzheimer’s plaques, known as neuritic plaques, have long been known to contain amyloid beta proteins. In fact, some proposed tests for Alzheimer’s involve testing the cerebral spinal fluid for elevated levels of amyloid beta.

Alzheimer’s has also been shown to have effects on the eye. Patients with the disease have been known to show evidence of retinal degeneration, which affects cells at the base of the optic nerve.

“There are clearly retinal effects of Alzheimer’s disease. The question is, is it mediated by amyloid beta?” Anderson said. “It’s a good bet. And it’s a testable assumption.”

One study conducted in the Netherlands, known as the Rotterdam Study, indicates that patients suffering from AMD are perhaps twice as likely to develop Alzheimer’s disease.

The protein amyloid beta also has many effects that could be logically linked to the cyclical immune response present in AMD. It is known to initiate the complement response and the inflammatory response. It also stimulates the secretion of special molecules called matrix metalloproteinases, which chew up the membranes between cells as well as angiogenic molecules, which encourage blood vessel growth. In advanced AMD, holes are found in Bruch’s membrane. Angiogenic molecules may be to blame for encouraging blood vessels to grow into these spaces, eventually leading to the wet form of AMD.

Into the Game

The discovery of amyloid beta and the likely discovery of other molecules common to both drusen and neuritic plaques give those at CSMD access to studies on Alzheimer’s in which the effects of these molecules have been painstakingly researched for years.

“Keeping on top of all this research and then keeping on top in our field is exceptionally difficult,” Anderson said.

A lot of research remains before amyloid beta can be definitively blamed for causing AMD, and the natural function of the amyloid beta protein is still unknown.

“Which is surprising, but true,” Anderson said.

Testing the effects of amyloid beta at CSMD will begin with cell cultures and experiments with transgenic rodents.

“This opens the door to the development of experimental models instead of just determining what the molecular composition of drusen is,” Anderson said. “There are many rodent models of Alzheimer’s, and I doubt anyone’s looked at the ocular status of those rodents.”

“This has now gone beyond a simple cytotoxic [cell-toxic] kind of story,” Johnson said. “Maybe we have the culprit. Maybe we have the bad guy. Maybe we don’t.”

Medical Solutions

Johnson and Anderson hope one day to be able to develop preventative measures for AMD. Advanced solutions may eventually include protein inhibitors or amyloid beta vaccines.

Current research on the disease suggests that vitamin supplements may reduce the risk of the disease. Studies show that anti-inflammatory drugs such as ibuprofen may help to prevent Alzheimer’s and may also serve to prevent AMD. But regular use of such drugs has its drawbacks.

“Maybe one day you’ll pop an anti-inflammatory and an antioxidant every day along with your vitamins and you’ll live to 150. You can’t do that right now because your kidneys would fail.”

Drug companies continue to investigate the problem.