Important New Insights into Alzheimer's Disease from Cultured Adult Induced Stem Cells from Alzheimer's Patients

When you take skin cells from an Alzheimer's patient, and turn them into neurons in culture, you can study these "Alzheimer's neurons" in detail in the lab. This ability to work with cultured human Alzheimer neurons from induced stem cells, on a day to day basis, will give scientists an intimate familiarity with the genetic and biochemical differences which lead to the pathological changes in the disease. And none too soon, because as western societies grow older, Alzheimer's is threatening to bankrupt their social medicine services.

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. _UCSD

This research is geared specifically toward Alzheimer's disease research, since Alzheimer's patients are the donours of the original cells being used. But the same approach can be used to culture a wide range of induced cell types, from patients with a wide range of disease types. In other words, this is just the beginning of a beautiful approach to bringing the full dynamics of human diseases into the laboratory for thorough study.

There is no way of predicting what possibilities may arise from this research over the long run.

3 Dimensional Bio-Cell Printing: Future Tissue & Organ Replacements

An optimized 3D inkjet printing process is demonstrated for structuring alginate into a tissue-like microvasculature capable of supporting physiological flow rates. Optimizing the reaction at the single-droplet level enables wet hydrogel droplets to be stacked, thus overcoming their natural tendancy to spread and coalesce. Live cells can be patterned using this process and it can be extended to a range of other hydrogels. _Advanced Materials

The dream is to be able to rapidly grow replacement tissues and organs, to allow for easy autologous replacement for a wide range of clinical reasons and circumstances -- including life extension regenerative treatments.

...Thus, it would take just under 2 hours to print a 1 cm thick tissue precursor graft and just over 5 h 30 to print a 3 cm thick kidney precursor. _Advanced Materials PDF

Swiss scientists are using a special inkjet printer to assemble three dimensional living constructs that resemble living tissues. They are still in the early stages of the research, but are achieving some interesting results.

They are working on a technique that should eventually allow them to “print” living constructs resembling human tissues in which cells can develop and interact in a coordinated and physiological manner. Their research results have recently been published in the scientific journal Advanced Materials.

“We have not yet created tissue, strictly speaking,” explains Professor Jürgen Brügger, head of EPFL’s Microsystems 1 Laboratory. “At this stage, we have essentially studied a way in which to structure biological materials in three dimensions; this research will improve cell culture and then will eventually be used as a base for creating tissues.”

...To make up a coherent whole, the cells need an environment that provides the right kinds of signals that induce very specific behavior in each of the cells – proliferation, migration, differentiation or death. In natural tissues, these signals come from molecules that make up a complex extracellular matrix (ECM). By studying the connections and communications taking place between cells and between cells and ECM molecules, the scientists were able to reconstruct this matrix and thus create a new kind of biological ink.

On a technical level, the researchers from EPFL’s two Microsystems Laboratories – under the leadership of professors Jürgen Brugger and Philippe Renaud – focused on developing a gel that could be used as a base from which the tissue could be constructed, as well as a strategy for printing droplets.

...Even though it will still be quite some time before tissue can be constructed, this technology could lead to very promising applications on the medium term. “ An exiting avenue would be to develop 3D constructs that function like human tissues and could be used as models for testing new drugs,” says Lutolf. “This is not only very interesting in a biological sense, but could also reduce the need for animal testing.” _Physorg

Learning to create life-like 3 dimensional cell cultures for research, and learning to create 3-D lab-made living tissues for replacement, are not quite the same things. But the two lines of research are likely to borrow from and contribute to each other, extensively.

This research used fibroblasts. Future research is likely to use a variety of stem cells and other precursor cells for various cell types.

Non-fluorescent NIH 3T3 fibroblasts were used in this printing as to be compatible with the fluorescent Live-Dead assay. The cells were suspended in culture medium supplemented with 0.8% wt. non-fluorescent alginate at a concentration of 1x10 6 mL -1 . Cells were inkjet printed onto 2% wt. gelatin substrates prepared with 0.9% wt. NaCl and 10 mM CaCl2, prepared in a 96-well plate. All cells were incubated for 4h before Live-Dead staining. _Advanced Materials

Living More of Your Time: Enjoying and Mastering Alcohol

A person may "live" between 70 and 80 years, but only truly experience a relatively few years of life. After subtracting the time a person spends either sleeping, intoxicated, in childhood / adolescence, or in declining senescence, very few optimally productive years of time may be left.

An herbal chemical has been discovered which may well allow us to reduce our impairment from alcohol intoxication, giving us more time to appreciate, enjoy, and profit from our lives.

Led by Jing Liang from the University of California, researchers began looking at different herbs that have natural anti-alcohol properties. They found descriptions of anti-alcohol properties of the Asian tree Hovenia dulcis that dated back to 659. These descriptions listed it as a prime hangover remedy.

The main ingredient in Hovenia dulcis is known as dihydromyricetin, or DHM. The team of researchers used rats to test out the effects. Rats react similar to humans when it comes to the effects of alcohol so they are a perfect candidate.

The rats were given the human equivalent of 15-20 beers in a time frame of under two hours. As expected, the rats passed out drunk and lost the ability to flip themselves over when placed on their back. Within an hour, the effects of the alcohol started to wear off and they were able to again control their bodies.

When the rats were given the same alcohol with a shot of the DHM, they still eventually lost the ability to flip over but it took a longer time period and they were able to recover from the effects in about 15 minutes.

The effects of the DHM went beyond that though. Two days after the alcohol consumption, the rats that were given the DHM showed less signs of hangover symptoms such as anxiety and seizures.

The other noted result was the reduction in addiction. When the rats were allowed to drink freely, they would gradually start consuming more. However, those rats that had received the DHM did not increase consumption. _MedicalXpress

The promise of this herb goes far beyond a treatment for alcohol addiction. It promises to give us back a great deal of the time that we voluntarily sacrifice to alcohol -- and the aftereffects of alcoholic indulgence.

How many bad choices do people make under the influence of alcohol, which lead to further destruction of our time and our lives -- as well as the premature ending of many innocent lives?

Earlier we looked at ways that we may safely reduce our sleeping time -- thus adding years to our lives. If we can also reduce much of the time wasted by intoxicants, we may well have added significantly more profitable time to our lives.

Life extension is about more than simply "living" more years. It is also about truly living the time that you are alive.

http://www.jneurosci.org/content/32/1/390.abstract: Article abstract link

Young Stem Cells In Old Mice Increased Lifespan

A special breed of mice lived up to three times longer than normal after University of Pittsburgh researchers injected them with stem cells from younger, healthy mice, according to a study being published today in the journal Nature Communications.

Working with mice that are bred to die prematurely, Pitt researchers led by Johnny Huard and Laura Niedernhofer dramatically increased the animals' lifespans by injecting them in the abdomen with young animals' muscle stem cells. _Post-Gazette

Keep in mind that this research was done in a special breed of mouse that is programmed to have a shorter lifespan. Additional research will be required to determine if normal ageing mice can benefit from similar treatment.

"We wanted to see if we could rescue these rapidly aging animals, so we injected stem/progenitor cells from young, healthy mice into the abdomens of 17-day-old progeria mice," Dr. Huard said. "Typically the progeria mice die at around 21 to 28 days of age, but the treated animals lived far longer – some even lived beyond 66 days. They also were in better general health."

As the progeria mice age, they lose muscle mass in their hind limbs, hunch over, tremble, and move slowly and awkwardly. Affected mice that got a shot of stem cells just before showing the first signs of aging were more like normal mice, and they grew almost as large. Closer examination showed new blood vessel growth in the brain and muscle, even though the stem/progenitor cells weren't detected in those tissues.

In fact, the cells didn't migrate to any particular tissue after injection into the abdomen.
"This leads us to think that healthy cells secrete factors to create an environment that help correct the dysfunction present in the native stem cell population and aged tissue," Dr. Niedernhofer said. "In a culture dish experiment, we put young stem cells close to, but not touching, progeria stem cells, and the unhealthy cells functionally improved." _MedXpress

Stem cells can conceivably be used for many purposes, in the treatment of ageing. In the case of the above research, the stem cells apparently secreted some type of hormonal growth factor which was lacking in the progeria mice.

But in future, more sophisticated uses of stem cells to treat ageing, stem cells will be used for tissue replacement, organ regeneration and replacement, humoral factor replacement, and probably other uses not yet discovered.