Alzheimer's-Where why and how

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Columbia University Medical Center, via Newswise.

3 ROOTS OF ALZHEIMER'S: 

Columbia University researchers have pinpointed 3 discoveries about Alzheimer's:

• Where it starts
• Why it starts there
• How it spreads.

Learn why this can help researchers treat Alzheimer's sooner and better

discoveries about Alzheimer's:

• Where it starts
• Why it starts there
• How it spreads.

Learn why this can help researchers treat Alzheimer's sooner and better. 

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Using high-resolution functional MRI (fMRI) imaging in patients with Alzheimer's disease and in mouse models of the disease, Columbia University Medical Center (CUMC) researchers have clarified three fundamental issues about Alzheimer's: where it starts, why it starts there, and how it spreads. In addition to advancing understanding of Alzheimer's, the findings could improve early detection of the disease, when drugs may be most effective. The study was published today in the online edition of the journalNature Neuroscience.

Alzheimer's disease starts in the entorhinal cortex (yellow). Using fMRI in mouse (left) and human (right) brains, the researchers provide evidence that the disease spreads from the entohrinal cortex (yellow) to other cortical regions (red) -- the perirhinal cortex and posterior parietal cortex. (Credit: Usman Khan/lab of Scott A. Small, MD, Columbia University Medical Center.)

"It has been known for years that Alzheimer's starts in a brain region known as the entorhinal cortex," said co-senior author Scott A. Small, MD, Boris and Rose Katz Professor of Neurology, professor of radiology, and director of the Alzheimer's Disease Research Center. "But this study is the first to show in living patients that it begins specifically in the lateral entorhinal cortex, or LEC. The LEC is considered to be a gateway to the hippocampus, which plays a key role in the consolidation of long-term memory, among other functions. If the LEC is affected, other aspects of the hippocampus will also be affected."

The study also shows that, over time, Alzheimer's spreads from the LEC directly to other areas of the cerebral cortex, in particular, the parietal cortex, a brain region involved in various functions, including spatial orientation and navigation. The researchers suspect that Alzheimer's spreads "functionally," that is, by compromising the function of neurons in the LEC, which then compromises the integrity of neurons in adjoining areas.

A third major finding of the study is that LEC dysfunction occurs when changes in tau and amyloid precursor protein (APP) co-exist. "The LEC is especially vulnerable to Alzheimer's because it normally accumulates tau, which sensitizes the LEC to the accumulation of APP. Together, these two proteins damage neurons in the LEC, setting the stage for Alzheimer's," said co-senior author Karen E. Duff, PhD, professor of pathology and cell biology (in psychiatry and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain) at CUMC and at the New York State Psychiatric Institute.

In the study, the researchers used a high-resolution variant of fMRI to map metabolic defects in the brains of 96 adults enrolled in the Washington Heights-Inwood Columbia Aging Project (WHICAP). All of the adults were free of dementia at the time of enrollment.

"Dr. Richard Mayeux's WHICAP study enables us to follow a large group of healthy elderly individuals, some of whom have gone on to develop Alzheimer's disease," said Dr. Small. "This study has given us a unique opportunity to image and characterize patients with Alzheimer's in its earliest, preclinical stage."

The 96 adults were followed for an average of 3.5 years, at which time 12 individuals were found to have progressed to mild Alzheimer's disease. An analysis of the baseline fMRI images of those 12 individuals found significant decreases in cerebral blood volume (CBV) -- a measure of metabolic activity -- in the LEC compared with that of the 84 adults who were free of dementia.

A second part of the study addressed the role of tau and APP in LEC dysfunction. While previous studies have suggested that entorhinal cortex dysfunction is associated with both tau and APP abnormalities, it was not known how these proteins interact to drive this dysfunction, particularly in preclinical Alzheimer's.

To answer this question, explained first author Usman Khan, an MD-PhD student based in Dr. Small's lab, the team created three mouse models, one with elevated levels of tau in the LEC, one with elevated levels of APP, and one with elevated levels of both proteins. The researchers found that the LEC dysfunction occurred only in the mice with both tau and APP.

The study has implications for both research and treatment. "Now that we've pinpointed where Alzheimer's starts, and shown that those changes are observable using fMRI, we may be able to detect Alzheimer's at its earliest preclinical stage, when the disease might be more treatable and before it spreads to other brain regions," said Dr. Small. In addition, say the researchers, the new imaging method could be used to assess the efficacy of promising Alzheimer's drugs during the disease's early stages.

The paper is titled, "Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease." The other contributors are Li Liu, Frank Provenzano, Diego Berman, Caterina Profaci, Richard Sloan and Richard Mayeux, all at CUMC.

The study was supported by grants from National Institutes of Health (AG034618, AG025161, AG07232, AG037212, NS074874, and HL094423.

Source:

Columbia University Medical Center, via Newswise.

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Journal Reference:

1. Usman A Khan, Li Liu, Frank A Provenzano, Diego E Berman, Caterina P Profaci, Richard Sloan, Richard Mayeux, Karen E Duff, Scott A Small. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nature Neuroscience, 2013; DOI: 10.1038/nn.3606

Abnormal Protein May Explain Loss of Smell With Alzheimer’s

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Doctor's Lounge

The protein kills nerve cells in the nose, animal study finds.

(HealthDay News) -- A loss of a sense of smell can be one of the earliest signs of Alzheimer's disease.

New research suggests that an abnormal form of a protein -- amyloid precursor protein, or APP -- which has been previously associated with the Alzheimer's disease may be to blame.

A study in mice found that animals genetically engineered to produce high levels of the abnormal protein experienced high levels of death in nerve cells in their nose compared to normal mice.

Researchers say the findings may explain why people suffering from the progressive illness often lose their sense of smell while the disease is still in its initial stages. They added this new insight might help doctors detect the condition early on.

"Deficits in odor detection and discrimination are among the earliest symptoms of Alzheimer's disease, suggesting that the sense of smell can potentially serve as a canary in the coal mine for early diagnosis of the disease," study leader Leonardo Belluscio of the U.S. National Institute of Neurological Disorders and Stroke, said in a news release.

"The changes taking place in the olfactory system as a result of Alzheimer's disease may be similar to those in other regions of the brain but appear more rapidly," he added.

APP has been detected in the nose nerve cells of some people with early onset Alzheimer's, a rare form of the disease that runs in families and strikes before age 65.

The researchers found mice making the mutated form of APP had four times as much olfactory nerve cell death at three weeks of age than normal mice.

When researchers blocked the production of high levels of the mutated protein, more olfactory nerve cells survived.

"Reducing APP production suppressed the widespread loss of nerve cells, suggesting that such disease-related death of nerve cells could potentially be stopped," explained Belluscio.

The study, published in the Sept. 28 issue of The Journal of Neuroscience, also found that the cells that died in the nose did not contain amyloid plaques, which are derived from APP. Plaques have long been believed to contribute to the death of nerve cells in the brains of people with Alzheimer's, leading to memory loss.

The researchers say the findings suggest that APP itself may be responsible for the death of nerve cells.

"Together, these results support the hypothesis that amyloid proteins are involved in the degeneration of the brain that occurs with Alzheimer's disease," Donald Wilson of New York University School of Medicine and the Nathan Kline Institute for Psychiatric Research, said in a news release from the journal.

"Further, they provide an exciting opportunity to explore how to prevent or reverse the events that lead to cell death and, ultimately, dementia," added Wilson, an olfactory system expert who was not involved in the study.

While more research is needed, it should be noted that studies involving animals often fail to produce similar results with humans.

More information

The National Institutes of Health provides more information on Alzheimer's disease.

SOURCE: Society for Neuroscience, news release, Sept. 27, 2011

Protein linked to Alzheimer's disease doesn't act alone

EurekAlert

Karen Mallet


GUMC researchers find APP needs to work with 'Reelin' protein to maintain healthy communication between brain neurons

Washington, DC – A team of U.S. investigators led by neuroscientists at Georgetown University Medical Center (GUMC) are steadily uncovering the role that amyloid precursor protein (APP) - the protein implicated in development of Alzheimer's disease - plays in normal brain function. In the June 10 issue of the Journal of Neuroscience, they discovered that APP interacts with another protein known as Reelin to promote development of abundant connections between brain neurons.

Reelin, named for mice that "reel" around when they don't have the protein, has been thought to be involved in stimulating growth of neuronal dendrites – the branching projections that transmit signals to other neurons. It also has been implicated in some brain disorders, but up until now, little was known about how Reelin interacts with APP.

Researchers say that showing that APP and Reelin work together doesn't have immediate implications for therapeutic treatment of Alzheimer's disease in humans, but they say the work helps provide the background necessary to understand finally why a brain veers toward the progressive memory loss seen in this devastating disease, which impacts 5.3 million people yearly in the U.S..

"In the last 20 years we have made tremendous progress in understanding how APP can become toxic. But I think the flip side is equally interesting: Why does APP even exist in the brain? We are only now just beginning to figure that out," says the study's senior author, G. William Rebeck, PhD, associate professor in the Department of Neuroscience at GUMC.

What has long been known is that mutations in the gene that produces..........read the whole article

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Study suggests how Alzheimer's attacks brain

Stuff.conz

US scientists proposed a new theory of how Alzheimer's disease kills brain cells they said opens new avenues of research into treatments for the fatal, brain-wasting disease.

They believe a chemical mechanism that naturally prunes away unwanted brain cells during early brain development somehow gets hijacked in Alzheimer's disease.

"The key player we're focusing on is a protein called APP," said Marc Tessier-Lavigne, executive vice president of research drug discovery at the US biotechnology company Genentech Inc , whose study appears in the journal Nature.

Tessier-Lavigne said amyloid precursor protein, or APP -- a key building block in brain plaques found in Alzheimer's disease -- is the driving force behind this process.

"We know that APP is...read the whole article

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