A New Hypothesis About Alzheimer's Disease

According to the hypothesis, the disease arises as a consequence of inflammation, which creates abnormal metabolites out of normal brain molecules.

These abnormal metabolites then modify "amyloid beta" proteins in the brain and cause them to misfold. Misfolded amyloid beta proteins are thought to be a major player in Alzheimer's disease, because they can accumulate into the fibrils and plaques that autopsies reveal in the brains of patients with the disease. These fibrils and plaques and their precursors are implicated in neuronal loss.

The inflammation process that creates these metabolites can be triggered by numerous stimuli, including infections that precede the onset of Alzheimer's disease by a significant amount of time -- perhaps years.

"If a certain inflammatory metabolite or family of metabolites confers risk later in life, then we need to know this, and we need to attack the problem," says Scripps Research Professor Jeffery W. Kelly, who is the Lita Annenberg Hazen Professor of Chemistry in The Skaggs Institute for Chemical Biology and vice president of academic affairs at Scripps Research.

Kelly and his Scripps Research colleagues present their new theory in an article that will be published in an upcoming issue of the journal Proceedings of the National Academy of Sciences.

A Progressive, Incurable Disease

Alzheimer's is a progressive neurodegenerative disease marked by memory loss, loss of language ability, loss of the ability to mentally manipulate visual information, poor judgment, confusion, restlessness, and mood swings. According to the Alzheimer's Disease Education and Referral Center, a service of the National Institute on Aging, Alzheimer's disease is now believed to inflict some 4.5 million people and is the most common form of dementia among older people in the United States. Currently, there is no cure for Alzheimer's and no way to slow the progression of the disease.

German doctor Alois Alzheimer discovered the disease in 1906, when he examined a post-mortem patient who had died with an unusual mental illness. Alzheimer found unusual clumps of protein or plaques in her brain. These plaques­made up of aggregated proteins called amyloid beta­are a clear sign of the disease, and the aggregation of amyloid beta protein is an accepted primary pathological marker for Alzheimer's.

But scientists have not been sure whether these fibrils are causing the disease or are simply a marker of it. By analogy, a tidal wave may cause massive destruction to a coastal area, but the tidal wave itself may have been caused by a distant earthquake undetected in that coastal area.

Kelly and his colleagues have studied the basic biology of Alzheimer's and related diseases for many years, looking for new treatment approaches. Now, they think they may have taken a significant step along this path by identifying the distant earthquake that causes Alzheimer's.

Basic Science Brings it All Together

Amyloid diseases are caused by the misfolding of proteins into structures that lead them to cluster together, forming microscopic fibril or plaques, which deposit in internal organs and interfere with normal function, sometimes lethally. In the case of Alzheimer's, these fibrils kill nerve cells in areas of the brain that are crucial for memory.

These diseases include Alzheimer's, Parkinson's, and a peripheral nervous system disease called familial amyloid polyneuropathy (FAP)­a collection of more than 80 rare amyloid diseases caused by the misfolding of the protein transthyretin (TTR), which the liver secretes into the bloodstream to carry thyroid hormone and vitamin A.

In the FAP diseases, mutations in the TTR protein are known to play a direct role in causing the disease. Basically, these mutations change the amino acid sequence of TTR, and these changes alter protein folding in such a way as to predispose the proteins to misfold and accumulate into microscopic fibrils, which can then grow into the protein plaques characteristic of FAP and other amyloid diseases.

However, in Alzheimer's disease, the cause of misfolding is not so obvious. A number of mutations are associated with rare forms of familial Alzheimer's, but not with most common cases (about 95 percent of the cases). This suggests there must be a more common cause of Alzheimer's disease, and Kelly has combined efforts with several of his colleagues at Scripps Research to find it.

A few years ago, Kelly started to think about traumatic head injuries, which are a major risk factor for later developing Alzheimer's disease. The body responds to such injuries with inflammatory reactions that cause the release of components of lipid membranes, such as cholesterol.

Kelly began to discuss this with his colleagues in The Skaggs Institute for Chemical Biology, Scripps Research President Richard A. Lerner, M.D., and Scripps Research Associate Professor Paul Wentworth, Jr., Ph.D. Lerner and Wentworth had recently discovered how inflammation can lead to the production of reactive oxygen species such as ozone, which can trigger pathological changes in other molecules in the body, like cholesterol.

In a paper last year, Lerner, Wentworth, and several colleagues described how ozone reacts with normal metabolites to produce toxic compounds during inflammatory processes taking place in the body. The scientists describe two such compounds, which they call the "atheronals." The scientists suggest these newly identified products are critical to the pathogenesis of the disease atherosclerosis because these atheronals were found in atherosclerotic plaques that were surgically removed from patients with atherosclerosis. (Atherosclerosis is a common vascular disease that increases the risk of heart attacks and strokes and is characterized by a hardening of the arteries over time due to deposits of fibrous tissue, calcium, fat, cholesterol, proteins, cells, and other materials on the inner "endothelial" walls of an artery).

This discovery made Kelly sit up straight when he first heard it because inflammation is increasingly seen as playing a role in neurodegenerative diseases. Also, there are a fair number of risk factors in common between the two diseases, including hypercholesterolemia and inflammation.

In their new study, Kelly and his colleagues suggest that inflammation in the brain could create a perfect storm in which cholesterol and lipids react with ozone and other inflammatory chemicals to produce abnormal reactive metabolites, which, in turn, modify the folding of normal amyloid beta protein. These modified amyloid beta proteins can catalyze misfolding in other unmodified amyloid beta proteins, starting an avalanche of misfolding that results -- perhaps years or decades later -- in Alzheimer's disease.

A New Way of Thinking About Disease in General

To examine the hypothesis that these metabolites may be the root cause of Alzheimer's, Kelly and his colleagues examined the post-mortem brains of Alzheimer's patients and compared these to age-matched controls.

They found evidence of atheronals in the brains of both the Alzheimer's patients and the control subjects. The levels of atheronals in the brains of the Alzheimer's patients were not significantly elevated, but this is not necessarily surprising. According to the new theory, the propagation of misfolding and the buildup of fibrils inside the brain does not depend upon continuous exposure to metabolite-modified proteins, but to exposure during a precipitating event that may occur a decade or more earlier. The creation of these metabolite-linked misfolding proteins is only the initiator of the fibril plaques.

Kelly and colleagues also performed experiments in the test tube and found that atheronals and lipid oxidation products have the ability to dramatically accelerate the misfolding of amyloid beta and to reduce the concentration of the protein needed for misfolding to take place to concentrations found in the brain.

This is an entirely new way of thinking about not only Alzheimer's disease, but disease in general. Historically, science has regarded disease as based on the up or down regulation of gene expression or protein function. But this theory suggests a new sort of pathology -- the creation of a reactive metabolite by inflammatory stress, leading to the modification of a protein, the aggregation of that protein over time, and the degeneration of function in the brain or whichever internal organ hosts the aggregation.

The inflammatory metabolite theory of Alzheimer's will be difficult to prove, admits Kelly, because the presence of these abnormal metabolites are hard to detect years after they initiated the aggregation. There is, so far, no smoking gun.

"Is [this theory] right? Time will tell," says Kelly. "That's how science works."

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The article, "Metabolite-initiated protein misfolding may trigger Alzheimer's disease" was authored by Qinghai Zhang, Evan T. Powers, Jorge Nieva, Mary E. Huff, Maria A. Dendle, Jan Bieschke, Charles G. Glabe, Albert Eschenmoser, Paul Wentworth, Jr., Richard A. Lerner, and Jeffery W. Kelly and appears in the online edition of the journal Proceedings of the National Academy of Sciences the week of March 15-19, 2004. The article will appear in print later this year. See: pnas.org/cgi/doi/10.1073/pnas.0400924101.

This work was supported by The Skaggs Institute for Chemical Biology and the Lita Annenberg Hazen Foundation.

About The Scripps Research Institute

The Scripps Research Institute in La Jolla, California, is one of the world's largest, private, non-profit biomedical research organizations. It stands at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases and synthetic vaccine development.