Alzheimer's neurons induced from pluripotent stem cells

Stem-cell-derived neurons, made from patients with Alzheimer's disease, provide a new tool for unraveling the mechanisms underlying the neurodegenerative disease. In this image, DNA is shown in blue, dendrites and cell bodies in red and endosomal markers Rab5 and EEA1 in green and orange, respectively. Credit: UC San Diego School of Medicine

Led by researchers at the University of California, San Diego School of Medicine, scientists have, for the first time, created stem cell-derived, in vitro models of sporadic and hereditary Alzheimer's disease (AD), using induced pluripotent stem cells from patients with the much-dreaded neurodegenerative disorder.

26 jan 2012--"Creating highly purified and functional human Alzheimer's neurons in a dish – this has never been done before," said senior study author Lawrence Goldstein, PhD, professor in the Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute Investigator and director of the UC San Diego Stem Cell Program. "It's a first step. These aren't perfect models. They're proof of concept. But now we know how to make them. It requires extraordinary care and diligence, really rigorous quality controls to induce consistent behavior, but we can do it."

The feat, published in the January 25 online edition of the journal Nature, represents a new and much-needed method for studying the causes of AD, a progressive dementia that afflicts approximately 5.4 million Americans. More importantly, the living cells provide an unprecedented tool for developing and testing drugs to treat the disorder.

"We're dealing with the human brain. You can't just do a biopsy on living patients," said Goldstein. "Instead, researchers have had to work around, mimicking some aspects of the disease in non-neuronal human cells or using limited animal models. Neither approach is really satisfactory."

Goldstein and colleagues extracted primary fibroblasts from skin tissues taken from two patients with familial AD (a rare, early-onset form of the disease associated with a genetic predisposition), two patients with sporadic AD (the common form whose cause is not known) and two persons with no known neurological problems. They reprogrammed the fibroblasts into induced pluripotent stem cells (iPSCs) that then differentiated into working neurons.

The iPSC-derived neurons from the Alzheimer's patients exhibited normal electrophysiological activity, formed functional synaptic contacts and, critically, displayed tell-tale indicators of AD. Specifically, they possessed higher-than-normal levels of proteins associated with the disorder.

With the in vitro Alzheimer's neurons, scientists can more deeply investigate how AD begins and chart the biochemical processes that eventually destroy brain cells associated with elemental cognitive functions like memory. Currently, AD research depends heavily upon studies of post-mortem tissues, long after the damage has been done.

"The differences between a healthy neuron and an Alzheimer's neuron are subtle," said Goldstein. "It basically comes down to low-level mischief accumulating over a very long time, with catastrophic results."

The researchers have already produced some surprising findings. "In this work, we show that one of the early changes in Alzheimer's neurons thought to be an initiating event in the course of the disease turns out not to be that significant," Goldstein said, adding that they discovered a different early event plays a bigger role.

The scientists also found that neurons derived from one of the two patients with sporadic AD exhibited biochemical changes possibly linked to the disease. The discovery suggests that there may be sub-categories of the disorder and that, in the future, potential therapies might be targeted to specific groups of AD patients.

Though just a beginning, Goldstein emphasized the iPSC-derived Alzheimer's neurons present a huge opportunity in a desperate fight. "At the end of the day, we need to use cells like these to better understand Alzheimer's and find drugs to treat it. We need to do everything we can because the cost of this disease is just too heavy and horrible to contemplate. Without solutions, it will bankrupt us – emotionally and financially."

More information: A patent application has been filed on this technology by the University of California, San Diego. For more information, go to: http://techtransfe … D/22199.html

Provided by University of California - San Diego

Nutritional intervention helps in mild Alzheimer's disease

A second clinical trial of the medical food Souvenaid confirmed that daily intake of the nutritional intervention improves memory in people with mild Alzheimer's disease (AD). Results of the trial - called Souvenir II - were presented at the 4th International Conference on Clinical Trials in Alzheimer's Disease (CTAD) in San Diego, California on Friday, Nov. 4, 2011 by Philip Scheltens, MD, PhD, Professor of Cognitive Neurology and Director of the Alzheimer Center at the VU University Medical Center in Amsterdam.

05 nov 2011--CTAD is sponsored by the University of California, San Diego School of Medicine and the European Alzheimer's Disease Consortium (EADC).

Souvenaid contains a patented combination of nutrients (Fortasyn Connect) specifically designed to stimulate the formation of nerve connections called synapses. Loss of synapses is thought by many Alzheimer's experts to be the underlying cause of memory loss and cognitive dysfunction in AD. Preclinical studies showed that the nutrients in Fortasyn Connect promote the growth of new brain synapses. Subsequently, in a study called Souvenir I, Souvenaid taken once per day over 12 weeks was shown to improve scores on standardized memory tests.

"I'm encouraged by the results of this second trial, but we need to do more analyses and further studies to fully understand the findings," said Scheltens. "These positive results give me the energy to go forward."

Souvenir II, conducted at 27 centers in six European countries, was designed to confirm that the benefits seen in Souvenir I persist for 24 weeks. The study also used a more comprehensive measure of memory, as well as other measures of brain activity. Participants in the blind study were randomly assigned to drink 125 ml. of Souvenaid or a control drink. Of the 259 subjects enrolled in the trial, 238 (91.9%) completed the study. Souvenaid was well tolerated, with 97% compliance among those who completed the study and a very favorable safety profile.

Memory performance was evaluated at baseline, 12 weeks and 24 weeks. The memory domain score of a Neuropsychological Test Battery (NTB) was the primary outcome parameter. This memory composite score was derived from the Rey Auditory Verbal Learning Test (immediate recall, delayed recall and recognition performance) and the Wechsler Memory Scale verbal paired associates test (immediate and delayed recall). Secondary outcomes resulting from the NTB were the executive function domain, total composite score and individual item scores.

During 24 weeks, memory composite scores from the Souvenaid group were significantly better than those from the control group. The significant effect on memory performance was confirmed by individual tasks of the NTB memory domain. Detailed analyses of secondary outcomes are still ongoing, including electroencephalogram (EEG) data as a measure of brain function. The EEG analysis, along with data from a magnetoencephalogram (MEG) sub-study may provide further understanding of the effect of Souvenaid on functional connectivity, thus investigating the hypothesis that Souvenaid can support synapse formation and function in mild AD.

Provided by University of California - San Diego

Mount Sinai researchers find new Alzheimer's disease treatment promising

Preliminary findings in Phase IIA trial point to natural compound NIC5-15's potential

New York, 13 july 2009 – Researchers at Mount Sinai School of Medicine have found that a compound called NIC5-15, might be a safe and effective treatment to stabilize cognitive performance in patients with mild to moderate Alzheimer's disease. The two investigators, Giulio Maria Pasinetti, M.D., Ph.D. , and Hillel Grossman, M.D., presented Phase IIA preliminary clinical findings at the Alzheimer's Association 2009 International Conference on Alzheimer's Disease (ICAD) in Vienna on Sunday, July 12.

NIC5-15's potential to preserve cognitive performance will be further evaluated in a Phase IIB clinical trial. Early evidence suggests that NIC5-15 is a safe and tolerable natural compound that may reduce the progression of Alzheimer's disease-related dementia by preventing the formation of beta-amyloid plaque, a waxy substance that accumulates between brain cells and impacts cognitive function. .

"With Alzheimer's disease affecting 5.2 million Americans, another 5 million with early-state disease, and nearly a half million new cases reported annually, treatments like NIC5-15 would make a significant difference in the lives of many Alzheimer's patients," said Dr. Pasinetti, Professor of Psychiatry, Professor of Neuroscience and Professor of Geriatrics and Adult Development, in the Department of Psychiatry at Mount Sinai School of Medicine. "We are hopeful that the follow up clinical study will support this preliminary evidence."

"There are no FDA-approved Alzheimer's disease modifying drugs available today," said Dr. Hillel Grossman, Assistant Professor of Psychiatry, Co-Director of the Clinical Research Core of the Alzheimer's Disease Research Center, and Clinical Director of the Mount Sinai Memory and Aging Center. "Current drugs approved for use help maintain cognitive function, but only for a limited time. NIC5-15 is part of a new class of natural compound we found to have the potential of precluding the generation of β-amyloid and, eventually, attenuating cognitive deterioration in preclinical models of Alzheimer's disease."

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The study was conducted at the Mount Sinai Alzheimer's Disease Research Center (ADRC), a nationally renowned center of excellence since 1984. ADCR is a comprehensive research facility and clinical program dedicated to the study and treatment of both normal aging and Alzheimer's disease. The Center is supported by the National Institute on Aging, a branch of the National Institutes of Health. Humanetics Corporation, manufacturers of NIC5-15, sponsored the study. Phase IIB clinical trials on NIC5-15 are expected to begin later this year.

Disclosure: Dr. Pasinetti has a patent pending for the use of NIC5-15 in the treatment of Alzheimer's disease. The patent application was filed on his behalf by the Mount Sinai School of Medicine. Dr. Pasinetti and the School of Medicine could benefit financially from the results of this trial.