Why Do Some People Get Alzheimer’s Disease but Others Do Not?


Everyone has a brain that has the tools to develop Alzheimer’s disease. Why therefore do some people develop Alzheimer’s disease (AD) while others do not? An estimated five million Americans have AD – a number projected to triple by 2050– the vast majority of people do not and will not develop the devastating neurological condition. What is the difference between those whole develop AD and those who do not?

Subhojit Roy, associate professor in the Departments of Pathology and Neurosciences at the University of California, San Diego School of Medicine, asked this exact question. In a paper published in the journal Neuron, Roy and colleagues offer an explanation for this question. As it turns out, in most people there is a critical separation between a protein and an enzyme that, when combined, trigger the progressive cell degeneration and death characteristic of AD.

“It’s like physically separating gunpowder and match so that the inevitable explosion is avoided,” says principal investigator Roy, a cell biologist and neuropathologist in the Shiley-Marcos Alzheimer’s Disease Research Center at UC San Diego. “Knowing how the gunpowder and match are separated may give us new insights into possibly stopping the disease.”

Neurologists measure the severity of AD by the loss of functioning neurons. In terms of pathology, there are two tell-tale signs of AD: a) clumps of a protein called beta-amyloid “plaques” that accumulate outside neurons and, b) threads or “tangles” of ‘tau” protein found inside neurons. Most neuroscientists believe AD is caused by the accumulation of aggregates of beta-amyloid protein, which triggers a sequence of events that leads to impaired cell function and death. This so-called “amyloid cascade hypothesis” puts beta-amyloid protein at the center of AD pathology.

Creating beta-amyloid requires the convergence of a protein called amyloid precursor protein (APP) and an enzyme that cleaves APP into smaller toxic fragments called beta-secretase or BACE.

“Both of these proteins are highly expressed in the brain,” says Roy, “and if they were allowed to combine continuously, we would all have AD.”

It sounds inexorable, but it doesn’t always happen. Using cultured hippocampal neurons and tissue from human and mouse brains, Roy and Utpal Das, a postdoctoral fellow in Roy’s lab who was the first author of this paper, and other colleagues, discovered that healthy brain cells largely segregate APP and BACE-1 into distinct compartments as soon as they are manufactured, which ensures that these two proteins do not have much contact with each other.

“Nature seems to have come up with an interesting trick to separate co-conspirators,” says Roy.

What then brings APP and BACE together? Roy and his team found that those conditions that promote greater production of beta-amyloid protein also increase the convergence of APP and BACE. Specifically, an increase in neuronal electrical activity, which is known to increase the production of beta-amyloid, also increased the convergence of APP and BACE. Post-mortem examinations of AD patients have shown that the cellular locations of APP and BACE overlap, which lends credence to the pathophysiological significance of this phenomenon in human disease.

Neurons were cotransfected with APP:GFP and BACE-1:mCherry, neurons were stimulated with glycine or picrotoxin (PTX), and the colocalization of APP and BACE-1 fluorescence was analyzed (see Experimental Procedures for more details). (B) Note that stimulation with glycine greatly increased APP/BACE-1 colocalization in dendrites (overlaid images on right). (C and D) Quantification of APP/BACE-1 colocalization. Note that increases in glycine-induced APP/BACE-1 convergence can
Neurons were cotransfected with APP:GFP and BACE-1:mCherry, neurons were stimulated with glycine or
picrotoxin (PTX), and the colocalization of APP and BACE-1 fluorescence was analyzed (see Experimental Procedures for more details).
(B) Note that stimulation with glycine greatly increased APP/BACE-1 colocalization in dendrites (overlaid images on right).
(C and D) Quantification of APP/BACE-1 colocalization. Note that increases in glycine-induced APP/BACE-1 convergence can

Das says that their findings are fundamentally important because they elucidate some of the earliest molecular events triggering AD and show how a healthy brain naturally avoids them. In clinical terms, they point to a possible new avenue for ultimately treating or even preventing the disease.

“An exciting aspect is that we can perhaps screen for molecules that can physically keep APP and BACE-1 apart,” says Das. “It’s a somewhat unconventional approach.”

Induced Pluripotent Stem Cells Used to Make Model System for Degenerative Eye Disease


Researchers from the laboratory of David Gamm, who is the director of the University of Wisconsin McPhearson Eye Research Institute have made patient-specific pluripotent stem cells to study and model an eye disease known as age-related macular degeneration.

Gamm and his colleagues focused on a rare eye disease called Best disease for their work. Best disease is also known as “vitelliform macular dystrophy,” and it is an inherited disease of the eye. Best disease is inherited as an “autosomal dominant” disease, which means that you only need one copy of the chromosome that carries the gene responsible for the disease to show symptoms and it occurs equally in males and females. The disease first makes its appearance in childhood, and results from abnormalities in the tissue in the very back of the eye, behind the neural retina; the retinal pigment epithelium (RPE).

Patients with Best disease show dysfunction of a protein called “bestrophin” and this messes up ion transport in the RPE cells. The result is abnormal accumulation of fluid and other rubbish in the RPE cells and in the space between the RPE and the neural retina. The accumulation of all this junk kills off photoreceptors in the neural retina and the patient’s vision goes south rather quickly.

Gamm wanted to construct a model system for Best disease, which such a model would also tell him more about age-related macular degeneration, which is the main cause of blindness in people over 50. To make his model, Gamm took skin cells from patients with Best disease and made induced pluripotent stem cells (iPSCs) from them. Once the iPSCs were established in culture, Gamm differentiated the stem cells into RPE cells.

Gamm had made iPSCs from patients with Best disease and siblings of the patients who did not have Best disease. The cultured RPEs made from iPSCs derived from Best disease patients displayed many of the features of RPEs in the eyes of patients with Best disease. The retinas of Best patients contain fluid-filled spots that have the appearance of scrambled eggs.

Gamm’s cultures RPE’s from Best patients showed this same pathology whereas the RPEs from patients without Best disease failed to show such changes. The cultured RPEs showed other abnormalities that had never been detected to date in retinal cells from Best patients. For example, one of the jobs of the RPE cells is to help recycle used visual pigments. The RPE cells engulf and digest disc-like vesicles that bud from the photoreceptors and degrade the materials in them. However, cultured RPEs from Best patients were slow to degrade visual pigments, and showed abnormalities in their calcium signaling and handling various types of cellular stresses.

According to Gamm, “This model gives us a chance to understand the biological effects of human gene mutations in a relatively expeditious manner. Continuing, Gamm said: “Ultimately, we hope the model will help us craft treatments to slow or reverse the course of Best disease.”

Hopefully, Gamm and other eye researchers can use a model such as Gamm’s to develop and refine treatments for such degenerative eye diseased. Gamm said that his “results give us some ideas where to look for therapies that would allow us to interfere with the disease process. And the stem cell model gives us a chance to test those therapies before trying them on patients.”

There is a human dimension to this work, since the patients who volunteered to provide the tissue for these experiments feel as though they are participating in helping develop a treatment that has plagued them for some time.

As Gamm said, “These family members know they’re not getting treated directly as a result of this study, but they’re doing it out of concern for the next generation. That brings peace to them, to know that they’re not passive victims of this disease, but instead, active players in the discovery process.”

This technique could almost certainly provide ways to make model systems for other types of eye diseases.