Alzheimer's Club

Stress and Alzheimer's disease
News-Medical.net - Sydney, Australia
Subjecting mice to repeated emotional stress, the kind we experience in everyday life, may contribute to the accumulation of neurofibrillary tangles, one of the hallmarks of Alzheimer's disease, report researchers at the Salk Institute for Biological Studies. While aging is still the greatest risk factor for Alzheimer's disease, a number of studies have pointed to stress as a contributing factor. "A long-term study of about 800 members of religious orders had found that the people who were most prone to stress were twice as likely to develop Alzheimer's disease, but the nature of the link between the two has been elusive," says Paul E. Sawchenko, Ph.D., a professor in the Neuronal Structure and Function Laboratory, who led a phalanx of Salk researchers contributing to the current study. The group's findings, detailed in this week's Journal of Neuroscience, suggest that the brain-damaging effects of negative emotions are relayed through the two known corticotropin-releasing factor receptors, CRFR1 and CRFR2, which are part of a central switchboard that mediates the body's responses to stress and stress-related disorders...

Certain Foie Gras Linked To Diseases Such As Alzheimer's And Arthritis, Animal Study Suggests
Science Daily (press release) - USA
University of Tennessee Graduate School of Medicine professor and researcher Alan Solomon, M.D., director of the Human Immunology and Cancer/Alzheimer's Disease and Amyloid-Related Disorders Research Program, led a team that discovered a link between foie gras prepared from goose or duck liver and the type of amyloid found in rheumatoid arthritis or tuberculosis. This experimental data has provided the first evidence that a food product can hasten amyloid development. Amyloidosis is a disease process involving the deposit of normal or mutated proteins that have become misfolded. In this unstable state, such proteins form hair-like fibers, or fibrils, that are deposited into vital organs like the heart, kidneys, liver, pancreas and brain. This process leads to organ failure and, eventually, death. There are many types of amyloid-related diseases in addition to rheumatoid arthritis, such as Alzheimer's disease, adult-onset (type-2) diabetes and an illness related to multiple myeloma called primary or AL amyloidosis, an illness that has been a particular focus of study in the Solomon laboratory. Foie gras is a culinary delicacy derived from massively enlarged fatty livers of ducks and geese. It is produced by gorging the fowl over several weeks. Solomon and his research team analyzed commercially sold foie gras from the U.S. and France and found that it contained a type of amyloid called AA. Amyloid deposits are commonly found in waterfowl, but this condition is noticeably increased in force-fed birds. In their study, mice prone to develop AA amyloidosis were injected or fed amyloid extracted from foie gras. Within eight weeks, a majority of the animals developed extensive amyloid deposits in the liver, spleen, intestine and other organs. Based on the findings of the study, Solomon and his team concluded that this and perhaps other forms of amyloidosis might be transmissible, like "mad cow" and other related diseases. Until now, no other infectious sources of food products have been found...

Alzheimer's associated enzyme can disrupt neural activity in brain
HULIQ - Hickory, NC, USA

An enzyme involved in the formation of the amyloid-beta protein associated with Alzheimer's disease can also alter the mechanism by which signals are transmitted between brain cells, the disruption of which can cause seizures. These findings from researchers at the MassGeneral Institute for Neurodegenerative Disorders (MGH-MIND) may explain the increased incidence of seizures in Alzheimer's patients and suggest that potential treatments that block this enzyme - called beta-secretase or BACE - may alleviate their occurrence. The report will appear in the journal Nature Cell Biology and is receiving early online release. "We have found a molecular pathway by which BACE can modulate the activity of sodium channels on neuronal cell membranes, says study leader Dora Kovacs, PhD, director of the Neurobiology of Disease Laboratory in the Genetics and Aging Research Unit at MGH-MIND. "That implies that elevated BACE activity may be responsible for the seizures frequently observed in Alzheimer's patients." Alzheimer's disease is characterized by plaques within the brain of the toxic amyloid-beta protein. Amyloid-beta is formed when the larger amyloid precursor protein (APP) is clipped by two enzymes - BACE and gamma-secretase - which releases the amyloid-beta fragment. Signaling impulses in nerve cells are transmitted via voltage-gated sodium channels, structures on the cell membrane that transmit electrochemical signal by admitting charged sodium particles into the cell's interior. Sodium channels consist of an alpha subunit, which makes up the body of the channel, and one or two beta subunits that help to regulate the channels' activity. Previous studies from Kovacs' team and others showed that the BACE and gamma-secretase enzymes that release amyloid-beta from APP also act on the beta2 subunit of neuronal sodium channels. The current study was designed to examine how this processing of the beta2 subunit may alter neuronal function. Lead author Doo Yeon Kim, PhD, and colleagues first confirmed that the beta2 subunit, similar to APP, can be acted on by BACE and gamma-secretase, releasing a portion of the beta2 molecule from the cell membrane. A series of experiments using brain tissue from animal models and from Alzheimer's patients revealed the following series of cellular events: Elevated levels of the free beta2 segment within the cell appear to increase production of the alpha subunits, but those molecules are not incorporated into new sodium channels on the cell surface. The resulting deficit of membrane sodium channels inhibits the passage of neuronal signals into and through the cells. Neuronal sodium-channel dysfunction is known to cause seizures in both mice and humans. In a supplement to the current paper the investigators present evidence that sodium channel metabolism is altered in the brains of Alzheimer's patients compared with non-demented individuals of similar age. "Our study suggests that the BACE inhibitors currently being developed to reduce amyloid-beta generation in Alzheimer's disease patients may also help prevent seizures by alleviating disrupted neural activity," Kovacs explains. "However, complete inhibition of BACE activity could interfere with the enzyme's normal regulation of sodium channels, so therapeutic strategies using those inhibitors will need to be carefully designed." Kovacs is an associate professor of Neurology at Harvard Medical School. -Massachusetts General Hospital.

Motion Sensors Used to Predict Alzheimer's Disease
FOX News - USA
The goal: Shave off that time by spotting subtle changes in mobility and behavior that Alzheimer's specialists are convinced precede the disease's telltale...

Discovery Made on Alzheimer's Disease
WLNS - Lansing, MI, USA
US researchers think they've figured out what is responsible for seizures suffered by Alzheimer's patients. Scientists found that an enzyme that contributes...
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New MRI Image Technique Predicts Early Onset Of Alzheimer's Disease
Medical News Today (press release) - UK
Using new MRI techniques to analyze tissue composition and structure in the brain, researchers from the University of Pennsylvania School of Medicine and the National Institute on Aging successfully detected mild cognitive disorder (MCI), a condition in which patients suffer mild memory problems and is often an early symptom of Alzheimer's disease (AD). Results of the research were published in a recent issue of Neurobiology of Aging."This is important because detecting this kind of brain abnormality in its early stages with these techniques could have pivotal importance for the early detection and management of AD," said lead author of the study Cristos Davatzikos, MD, Chief of the Biomedical Image Analysis Section in Penn's Department of Radiology. "The diagnostic power of this technique could work hand-in-hand with the new drugs currently under development that target the early stages of AD before irreversible brain tissue damage sets in."In the first-of-its-kind study, researchers created a unique picture of patients' brains by combining and analyzing MRI images measuring the density and volume of various different tissues and their spatial distribution within the brain. From these images patterns associated with MCI were detected. Using this technique, researchers were able to not only to detect, with 100 % accuracy, those patients in the study with cognitive impairment from those with normal cognitive function, but also those predicted, with 90 percent accuracy, those patients with increasing onset of MCI, thereby demonstrating the diagnostic power of the new tool...

CoMentis Receives FDA Clearance to Begin Human Clinical Trials for Its Disease-Modifying Alzheimer's Therapy: Highly Potent Beta-Secretase Inhibitor to Enter the Clinic
Market Wire (press release) - USA
SOUTH SAN FRANCISCO, CA--(Marketwire - June 18, 2007) - CoMentis, Inc., a privately held biopharmaceutical company, announced today it is initiating a Phase I first-in-man study of its proprietary, orally bioavailable, small-molecule beta-secretase inhibitor CTS-21166, which is being developed as a disease-modifying treatment for Alzheimer's disease (AD). In preclinical studies, CTS-21166 exhibits excellent efficacy, selectivity, brain penetration and pharmacologic activity. "This is a significant achievement for CoMentis and for Alzheimer's disease drug development," stated W. Scott Harkonen, M.D., President and Chief Executive Officer. "CTS-21166 is an entirely new approach to the treatment of AD because it is a disease-modifying agent targeting beta-secretase, a critical enzyme involved in the pathogenesis of Alzheimer's disease, and it has the potential to become the first-in-class therapeutic agent." The CoMentis initial Phase I trial in healthy volunteers is designed as a dose escalation study to measure the safety, tolerability and pharmacokinetics of CTS-21166 following intravenous administration. Forty-eight subjects will receive one of several different doses or placebo. The company expects to begin generating human clinical data by the end of 2007 and to begin Phase II studies in Alzheimer's patients in 2008. Beta-Secretase and Alzheimer's Disease: Drs. Jordan Tang and Arun Ghosh, two of the scientific founders of CoMentis, are pioneers in the field of aspartic proteases. Since publication of the first beta-secretase inhibitor in 2000, Dr. Tang has led the characterization of this enzyme's role in Alzheimer's disease and Dr. Ghosh has led the construct of drug candidates to inhibit its activity. The action of this enzyme on the amyloid precursor protein leads to the formation of plaques in the brain and is implicated in the development of Alzheimer's disease. Inhibition of beta-secretase reduces beta amyloid production and could slow the progression of Alzheimer's disease. CTS-21166 is the first of several highly selective and potent beta-secretase inhibitors being developed by CoMentis that are highly active in preclinical models of Alzheimer's disease. "This is the most exciting target today for intervention in the pathogenesis of Alzheimer's disease," said Dr. Tang, who holds the J.G. Puterbaugh Chair in Medical Research at the Oklahoma Medical Research Foundation. "Beta-secretase is involved at a very early stage in the disease, and if we could block the activity of this enzyme, we could prevent many of the harmful steps that follow and drastically reduce the impact of Alzheimer's disease." About CoMentis: CoMentis, Inc. has its headquarters in South San Francisco, with research operations in both South San Francisco and Oklahoma City. The company is engaged in the discovery and development of small-molecule drugs to treat diseases such as Alzheimer's disease, age-related macular degeneration (AMD) and cognitive disorders. The company has two fundamental technology platforms: (i) aspartic protease inhibitors, including beta-secretase inhibitors for Alzheimer's disease; and (ii) nicotinic acetylcholine receptor (nAChR) agonists and antagonists for the treatment of angiogenesis mediated diseases and cognitive disorders. Originally founded in 2004 as Athenagen, Inc., the company was re-named CoMentis following the August 2006 merger with Zapaq, Inc., which created a leading neurovascular disease franchise. Zapaq was founded in 2001 by Jordan Tang, Ph.D., of the Oklahoma Medical Research Foundation, and Arun Ghosh, Ph.D., now at Purdue University, both experts in the field of aspartic proteases. In 2000, Dr. Tang's groundbreaking discovery of beta-secretase, an aspartic protease which is a critical enzyme in beta amyloid production, was published in Proceedings of the National Academy of Sciences.

CPAP Improves Sleep in Patients With Alzheimer's Disease, Sleep-related Breathing Disorder: Presented at SLEEP
DG News - USA
WESTCHESTER, IL -- Patients with both Alzheimer disease and a sleep-related breathing disorder (SRBD) experience disrupted sleep, resulting in increased nocturnal awakenings and a decreased percentage of REM sleep.However, in another example of the effectiveness of continuous positive airway pressure (CPAP), CPAP has been found to reduce the amount of time spent awake during the night, increase the time spent in deeper levels of sleep, and improve oxygenation, according to research presented at the 21st Annual Meeting of the Associated Professional Sleep Societies (SLEEP).The study, conducted by Jana R. Cooke, MD, of the University of California at San Diego, focused on 48 adults, with an average age of 77.8 years, with Alzheimer disease and an SRBD. It was discovered that treating the sleep-related breathing disorder with CPAP resulted in these patients spending less time awake during the night as well as sleeping deeper."In general, improved sleep is associated with improvements in quality of life," said Cooke. "Clinicians should consider CPAP treatment for Alzheimer disease patients with a sleep-related breathing disorder, as the potential benefits may be significant."Scientific evidence shows that CPAP is the best treatment for obstructive sleep apnea (OSA). CPAP provides a steady stream of pressurized air to patients through a mask that they wear during sleep. This airflow keeps the airway open, preventing the pauses in breathing that characterize OSA and restoring normal oxygen levels. Source: American Academy of Sleep Medicine.

Breakdown of myelin may be the cause of Huntington's disease
News-Medical.net - Sydney, Australia
Last month, Dr. George Bartzokis, director of the UCLA Memory Disorders and Alzheimer's Disease Clinic, suggested in the journal Alzheimer's & Dementia that the breakdown of a type of myelin that develops late in life promotes the buildup of toxic amyloid plaques long associated with Alzheimer's disease. Myelin is the insulation that wraps around nerve axons in the brain. Now, in a new report currently online in the journal Neurochemical Research, Bartzokis turns his attention to Huntington's disease. Again, he suggests that a breakdown of myelin is the cause, but with a twist it is the myelin that develops early in the formation of the brain that breaks down prematurely and eventually leads to the disease's symptoms. Huntington's disease (HD) is a rare, inherited neurological disorder that ultimately deprives individuals of their ability to control their movement, behavior and thinking. It affects approximately 30,000 people in the U.S., with another 150,000 at risk. While it is known that HD is caused by a mutation in a gene called Huntingtin (Htt), the exact mechanism by which the Htt gene causes or contributes to neuronal cell death and HD symptoms remains unclear. Bartzokis research suggests it is Htt's affect on myelin that may prove to be the cause. The earliest parts of the developing brain include systems of neurons that control movement and behavior. These neurons have long axons finger-like projections that serve as the primary transmission lines of the nervous system covered with thick myelin sheaths. The sheaths are nourished by an ongoing supply of a protein called brain-derived neurotrophic factor, which travels down a neuron's axon. Bartzokis believes the Htt gene interferes with this nourishment-delivery system, resulting in a breakdown of the myelin that depends on it. That, in turn, disrupts cell signaling, which results in the neuron's death. The problem is compounded by the continual production of other cells that continue to make myelin. In HD, increasing numbers of these cells, called oligodendrocytes, are produced in an attempt to remyelinate axons whose myelin sheaths have broken down. This results in strikingly elevated numbers of oligodendrocytes years before the appearance of HD symptoms. Such elevation is detrimental because oligodendrocytes are rich with iron, which, while required for myelination, is also a well-known catalyst of free-radical-induced tissue damage. Iron accumulates during normal aging, and abnormal iron metabolism is believed to be involved in many human disorders. This is true for both highly prevalent, chronic disorders of aging, such as Alzheimer's and Parkinson's diseases, and acute disorders, such as stroke, where the extent of tissue damage is also related to iron levels. To spot myelin destruction, neuron death and iron accumulation in the brains of HD subjects, Bartzokis used two magnetic resonance imaging (MRI) machines operating at different field strengths. Measurements of myelin breakdown and iron content were taken from the brains of 11 HD subjects and compared to a control group of 27subjects. Bartzokis found that both the breakdown and the iron accumulation matched the typical progression of the disease from early to late myelinating regions. Thus, according to Bartzokis, earlier myelinated axons, such as the ones controlling movement, bear the brunt of damage from the mutant gene in the disease. And the early symptoms of Huntington's are problems with controlling movement, behavior and eventually thinking," he said. The implications of this are important, Bartzokis noted, since there is a decades-long period during which therapeutic interventions could modify the course of the disease, long before clinical evidence such as behavioral, cognitive and motor problems appear. Thus, it may be possible to develop medication that could be administered in the very early stages using non-invasive in vivo neuroimaging markers of both myelin breakdown and levels of iron. Source: http://www.ucla.edu/