Alzheimer's Club

Breakthrough discoveries are pushing back the origins of Alzheimer's disease to an early breakdown in trafficking within brain cells, according to researchers at the Weill Medical College of Cornell University in New York City.

Experts have long known that a buildup of beta-amyloid protein "plaques" around and between neurons is a hallmark of Alzheimer's disease.

But they've also known that neurological decline can occur prior to this extra-cellular buildup.

"Our work is showing that long before this extracellular phenomenon occurs, beta-amyloid is building up inside neurons — specifically, on intracellular trafficking structures called multivesicular bodies," explained Gunnar Gouras, M.D., director of the Laboratory of Alzheimer's Disease Neurobiology and associate professor of neurology and neuroscience at Weill Cornell Medical College.

"In our latest study — conducted using brain cells from mice engineered to develop an Alzheimer's-like illness — we find that this gradual accumulation of beta-amyloid hinders the intracellular trafficking of neural receptors in a very specific way," he said.

"The brain cell isn't killed, but it is impaired in its function. And all of this occurs long before we see any evidence of plaque buildup outside the cell," Gouras said.

He said the work is greatly expanding our understanding of the origins of Alzheimer's disease, and pointing to new ways to fight it.

The findings appear in the April 26 issue of the Journal of Neuroscience.

According to the Alzheimer's Association, more than 4 million Americans now suffer from Alzheimer's disease, with that number expected to quadruple by mid-century. Right now, a few drugs can temporarily ease some illness symptoms, but there is no effective treatment or cure for Alzheimer's.

For a long while, scientists blamed the disease on a clumping of beta-amyloid plaques between cells. But research conducted at Weill Cornell and elsewhere has pushed back the origins of Alzheimer's disease to events occurring inside the cell.

In their latest study, Gouras' team used cell biological approaches to examine nerve cells extracted from the brains of "transgenic" mice — mice genetically engineered to develop a disease very similar to Alzheimer's.

The brain cells were extracted long before the mice developed symptoms indicating advanced disease.

Viewed by electron microscopy, the Weill Cornell researchers detected a buildup of beta-amyloid at the outer membrane of an intracellular trafficking structure called the "multivesicular body."

"The multivesicular body is an endosome — a kind of cargo-carrying body that's used late in endocytosis, the process by which the cell internalizes nutrients and other substances coming in from outside," explained lead researcher Claudia Almeida, M.S., who was a graduate student at the time of the study.

She and her colleagues give much of the credit to their understanding of the multivesicular body to Frederick Maxfield, Ph.D., chairman of the department of biochemistry at Weill Cornell, and a renowned pioneer in endocytosis research.

Beta-amyloid buildup around the multivesicular body came as no surprise, however — the team had first discovered this back in 2002.

"The question for us now was 'How might this abnormal buildup impair nerve cell function?' " Almeida said.

To find out, the researchers used a fluorescent "tag" to track the progress of a specific protein — in this case, epidermal growth factor (EGF) — as it made its way through the endocytosis process.

"We saw no impairment during early endocytosis, but as soon as we got to the later stages, when multivesicular bodies come into play, we spotted an accumulation of EGF in the cell," Gouras said.

Why might this be happening? According to the researchers, beta-amyloid-linked impairment in the function of multivesicular bodies seems to "gum up the works" when it comes to an important trafficking mechanism called the ubiquitin-proteasome system.

"This system used to be thought of as the cell's 'garbage disposal' — cutting up and ridding the cell of its biochemical waste," explained co-researcher Reisuke Takahashi, M.D., Ph.D., a pathologist researcher in Gouras' lab. "But, increasingly, investigators are realizing that it also has a crucial role to play in trafficking and even synaptic processes."

In fact, a breakdown in the ubiquitin-proteasome system has long been implicated in Parkinson's disease and other degenerative brain diseases.

"Alzheimer's has always been the 'odd man out' here," Gouras said, "but our work suggests it's maybe time to include Alzheimer's on that list."

The bottom line: "We now know that intracellular beta-amyloid buildup is associated with a destruction of specific processes within nerve cells - even in the absence of extracellular plaque accumulation," Gouras said.

The finding "opens a new window on the causes of Alzheimer's disease and — potentially — new targets that researchers might focus on to help prevent it in its earliest stages," he added.

The study was supported by grants from the Alzheimer's Association, the American Health Assistance Foundation and the National Institutes of Health.

This information was provided by NewYork-Presbyterian Hospital.

Source: Cellular origins of Alzheimer's. myDNA News (4 May 2006) [FullText]

A medical researcher who grew up in Manchester is trying to get other researchers interested in what he calls a "truly revolutionary notion," that the bacterium that causes Lyme disease may also be at the root of many cases of Alzheimer's disease.

A scientific journal called "Medical Hypotheses" this week published on the Internet the second in a series of papers in which the researcher, Dr. Alan B. MacDonald, sets forth his ideas on the subject.

"Medical Hypotheses" says in a description of its aims and scope that it will publish "radical ideas, so long as they are coherent and clearly expressed."

MacDonald, who works as a pathologist at a Long Island hospital, makes clear that the title of the journal aptly describes his idea: It is a hypothesis, meaning an unproven theory used to design further experiments to confirm or refute it.

But if MacDonald's idea should prove out, it would open new possibilities for prevention and treatment of Alzheimer's disease, in that bacterial infections can be treated with antibiotics.

Lyme disease is caused by a spirochete, a corkscrew-shaped bacterium, known as Borrelia burgdorferi. It was first identified in the United States as a result of an outbreak of arthritis-like symptoms in 1975 in Lyme, Old Lyme, and East Haddam, Conn.

Lyme disease is also known to have neurological effects in some cases.
Alzheimer's is a common neurological disease in which the mental abilities of patients steadily deteriorate, leading ultimately to their deaths. It primarily afflicts the elderly but can strike younger people as well.

MacDonald has been interested in the possibility of a connection between the Lyme spirochete and major neurological diseases, including Alzheimer's, for more than two decades. But, while working as a pathologist, a doctor who specializes in diagnosing diseases in tissues removed from the body or studied during autopsies, he hasn't always been in a position to do research on the subject.

MacDonald's new paper is based on research showing that the spirochete that causes Lyme disease can take on the rounded form of a cyst under adverse conditions, such as starvation, an acidic environment, or attack by antibiotics.

"Anything that needs to survive adversity will round up and form a cyst," he said in a telephone interview from Long Island, where he works at St. Catherine of Siena Medical Center in Smithtown, N.Y.

He suggests the possibility that these rounded forms of the spirochete might be the "root cause" of the rounded structures called plaques found in the brains of Alzheimer's patients. He says there are structural and other similarities between Lyme cysts and Alzheimer's plaques.

Moreover, MacDonald says, he has found evidence in seven of 10 known Alzheimer's brains of "transfection" with DNA from the Lyme spirochete. Transfection is the incorporation of a piece of DNA from an alien species into human DNA.

He has used this information to design a DNA probe, which he then used on the brain of a deceased Alzheimer's patient who was known to have had Lyme disease. The DNA probes showed a pattern similar to the distribution, size, and shape of Alzheimer's plaques, according to his article.

MacDonald says in the article that some have suggested that the overlap between evidence of Lyme infection and evidence of Alzheimer's may be a coincidence, in that both diseases are relatively common.

But he suggests that that argument may be refuted if it can be shown that Lyme DNA regularly appears at the site of the tissue injuries that define Alzheimer's disease.

"DNA of the alleged perpetrator at the scene of the crime constitutes 'molecular proof'" that the Lyme spirochete causes Alzheimer's disease, he writes.

Dr. Christopher H. van Dyck, the director of the Alzheimer's disease research unit at the Yale University
School of Medicine, said Friday that MacDonald's hypothesis "sounds speculative but interesting. It probably is worthy of additional research."

He said there is known to be more than one cause of Alzheimer's disease.

Van Dyck, who is chairman of the medical scientific advisory committee of the Alzheimer's Association's Connecticut chapter, suggested that one focus of additional research might whether Alzheimer's disease is more common in areas where Lyme disease is found.

"There's no way it can be the cause of all Alzheimer's disease," van Dyck said. "There are genetic mutations that are known to cause Alzheimer's disease."

Source: Alex Wood. A truly revolutionary notion:'Medical researcher with ties to Manchester studies possibility of Lyme disease-Alzheimer's link. Journal Inquirer(5 May 2006) [FullText]

PACIFIC PALISADES, Calif. A 76-year-old woman suffering from Alzheimer's disease who walked away from her Pacific Palisades home was found unharmed Friday in a neighbor's home, police said.

Janet Serra had last been seen around 5:30 p.m. Thursday at her home in the 700 block of Ocampo Drive, said Officer Robert Ferrer of the Los Angeles Police Department's West Los Angeles Station.

Shortly after 9 Friday morning, Serra was found in a neighbor's home, said LAPD Lt. Paul Vernon.

"She had wandered into (the) neighbor's home and fell asleep on a bed," Vernon said. "The neighbors were not home. They found her this morning." It was unclear if the woman knew the neighbors, Vernon said.

Source: Missing Woman, 76, Found In Neighbor's Bed. CBS (5 May 2006) [FullText]

Alzheimer's disease describes a condition named after its discoverer, Alois Alzheimer. In 1907 he wrote a textbook study of a woman of 51 who had died of dementia, and whose brain he had subjected to microscopic analysis.

The examination showed changes Alzheimer had never witnessed before. Parts of the brain showed tangling and other parts showed clumping of brain matter. Later research showed more "younger" people who had died of dementia who displayed the same brain abnormalities. This came to be known as Alzheimer's disease.

It was later found that this type of dementia occurred far more often in older people, with their brains showing the same abnormalities at microscopic level.

However, at this time, Alzheimer's disease was a diagnosis only applied to younger sufferers, since these formed the basis of Alois Alzheimer's research. Older sufferers were labeled with pre-senile dementia or senile dementia of the Alzheimer type (SDAT).

Nowadays, with dementia in younger people being quite uncommon, it is usual for the term Alzheimer's disease to describe this entire group, right across the age range.

'Alzheimer's disease' is a deceptively simple label for a complicated set of symptoms which are hard to describe in their fullness without direct personal experience of such in another. A suitably evocative description is "A living death", while more prosaic medical terminology cites "the slow onset of memory loss with a gradual progression to a loss of judgement and changes in behavior and temperament."

The Royal College of Physicians describes Alzheimer's disease in more detail, defining dementia as fundamentally "the global impairment of higher functions", listing its impact on memory, daily problem-solving ability, the performance of learned perceptuo-motor skills (such as washing, dressing, and eating), appropriate use of social skills, and control of the emotional reactions, all of which occur under the influence of an increasingly clouded consciousness which is sadly typical of Alzheimer's.

Memory loss is of course the most obvious feature of Alzheimer's disease, but early on it can pass undetected as sufferers often manage to cover it up. The most recent memories go first, the distant past or long-term memory holding out until the disease has become quite advanced. The short-term memory covers recent events, such as those taking place in the last hours or days, even weeks, and it is this which Alzheimer's sufferers have real problems with, and whose failure can signify the onset of Alzheimer's disease.

Because memory loss is central to Alzheimer's disease and can easily be tested for, memory tests are an important diagnostic tool used to assess Alzheimer's sufferers.

One formerly common test was to ask suspected Alzheimer's sufferers a list of questions which probed both their long and short-term memory.

Typical questions included: How old are you, what is your date of birth, what day is it today, what month is it, what year is it, when was the First World War, what is the name of the Prime Minister, where are you now, count back from 20 to 1, and finally the sufferer would be given an address and asked to repeat it back 5 mnutes later.

If the suspected Alzheimer's sufferer is co-operative, having been asked the questions in a respectful and unintrusive way, this is a relatively easy and inexpensive test to carry out, and which can yield useful pointers as to which parts of the memory may be problematic. Not only will long or short-term memory problems (or both) show up, but also potential orientation issues.

However, a low score by itself doesn't prove either dementia or Alzheimer's disease, as not everyone will know all the answers regardless of the state of their memory. The test is simply a guide to show that there may be a problem that needs further investigation. The above is an overview of aspects of the very complex and involved medical condition known as Alzheimer's disease.

Jay George is a writer/publisher on health matters. "Managing Alzheimer's Disease" is an e-book offering a wealth of background information on the condition, as well as highly practical care tips. See: http://www.ManagingAlzheimers.net

Source: Jay George. Alzheimers Disease: A History, Plus Memory Testing Methods. DailyIndia.com (3 May 2006) [FullText]

Researchers from the Flanders Interuniversity Institute for Biotechnology (VIB) connected to the University of Antwerp are the first to show that the quantity of amyloid protein in brain cells is a major risk factor for Alzheimer's disease. Amyloid protein has already been known to be the primary component of the senile plaques in the brains of patients.

The new discovery demonstrates that the greater the quantity of the protein that is produced, the younger the dementia patient is. Alzheimer's disease Alzheimer's disease is a memory disorder that affects up to 70% of all dementia patients. In Belgium, about 100,000 people suffer from this disease.

The disease gradually destroys brain cells in the deep areas of the brain that are responsible for memory and knowledge. Ever since the disease was first reported by Alois Alzheimer − 100 years ago now − scientists have been searching diligently for ways to treat it.

Amyloid plaque formation plays a key role Genetic research has previously shown a direct connection between amyloid protein and the development of senile plaques and loss of cells. Amyloid protein originates when it is cut by enzymes from a larger precursor protein.

In very rare cases (fewer than 1 in 1000 patients), mutations appear in that amyloid precursor protein, causing it to change shape and be cut differently. The amyloid protein that is formed now has different characteristics, causing it to begin to stick together and precipitate as amyloid plaques. The development of amyloid plaques in the brain tissue of Alzheimer patients is a central factor in the search for a therapy for Alzheimer's disease.


A lot or not much of the amyloid precursor protein is a risk factor The fact that patients with Down syndrome get Alzheimer's disease shows that the quantity of the amyloid precursor protein contributes to the disease: in fact, patients with Down syndrome have 3 copies of the gene (or hereditary code) for the amyloid precursor protein and therefore produce 150% instead of 100% of the protein.

So, Jessie Theuns and her colleagues, under the direction of Christine Van Broeckhoven, hypothesized that the quantity of amyloid precursor protein might also play a role in Alzheimer's disease. The geneticists from Antwerp systematically studied the hereditary code that is responsible for controlling the expression of the gene (= promoter).

Biological processes in our body are strictly regulated, primarily by closely controlling the amount of each protein that is produced. The promoter of a gene has the most important control function in this process.

In younger Belgian and Dutch Alzheimer's patients (younger than 70), the researchers found genetic variations in the promoter thatincreased the gene expression and thus the formation of the amyloid precursor protein. These variations in the promoter that increase expression occur up to 20 times more frequently (2 per 100 patients) than the mutations in the precursor protein that change the shape. Furthermore, there is a connection with the age at which the symptoms are first detected: the higher the expression (up to 150% as in Down syndrome), the younger the patient (starting between 50 and 60 years of age).

Thus, the amount of amyloid precursor protein is a genetic risk factor for Alzheimer's disease in the ageing process.

Prospects for tests and treatments

These new findings lead to a new understanding: namely, that the quantity of the amyloid precursor protein, and thus of the amyloid protein, in brain cells contributes significantly to the risk of contracting Alzheimer's. This discovery will have to be taken into account in diagnostic tests and in the search for new medicines.

Source: EurekAlert & The Hindu (21 April 2006) [FullText]