A study published this week in the Journal of Neuroscience shows that the compound epothilone D (EpoD) is effective in preventing further neurological damage and improving cognitive performance in a mouse model of Alzheimer’s disease (AD). The results establish how the drug might be used in early-stage AD patients.
…EpoD acts by the same microtubule-stabilizing mechanism as the FDA-approved cancer drug paclitaxel (Taxol™). These drugs prevent cancer cell proliferation by over-stabilizing specialized microtubules involved in the separation of chromosomes during the process of cell division. However, the Penn researchers previously demonstrated that EpoD, unlike paclitaxel, readily enters the brain and so may be useful for treating AD and related disorders.
After three months of receiving EpoD, additional tau clumps did not form in the brains of the aged AD mice, and nerve-cell function was increased compared to the AD mice that did not receive drug. What’s more, the EpoD-treated mice showed improvements in learning and memory. Importantly, the doses of EpoD that resulted in these benefits were much lower than had previously been used in Phase II clinical testing of EpoD in cancer patients. The investigators observed no side-effects — including the suppression of the immune system and peripheral nerve damage — in the transgenic mice that received EpoD. _UPennNews
Most approaches to treating Alzheimer’s dementia aim to either affect the levels of neurotransmitters in the brain — particularly acetylcholine — or to decrease accumulation of amyloid beta protein.
The idea of over-stabilising neurotubules to prevent tau tangles from forming in early stage Alzheimer’s is an intriguing approach, and dates to earlier studies attempting to discover the true etiological origins of Alzheimer’s. More from a 2011 study published in The Journal of Neuroscience:
Alzheimer’s disease (AD) pathology is characterized by senile plaques (SPs) and neurofibrillary tangles (NFTs) (Selkoe, 2001). SPs are extracellular deposits of amyloid-β (Aβ), a 3–4 kDa peptide derived from proteolytic cleavage of the amyloid precursor protein (APP) by β-site APP cleavage enzyme 1 (BACE) (Hussain et al., 1999; Sinha et al., 1999; Vassar et al., 1999; Yan et al., 1999) and the presenilin (PS)-containing γ-secretase complex (De Strooper et al., 1998; Wolfe et al., 1999). NFTs are intracellular accumulations of hyperphosphorylated tau (Lee et al., 2001). About 5% of AD cases are linked to pathogenic mutations in APP, PS1, or PS2 genes (Selkoe, 2001). Tau gene mutations are pathogenic for familial frontotemporal lobar degeneration characterized by tau pathology without SPs, indicating that tau abnormalities alone cause neurodegenerative disease (Lee et al., 2001). _Journal of Neuroscience 25 May 2011, 31(21): 7691-7699; doi: 10.1523/JNEUROSCI.6637-10.2011
Note that researchers are still attempting to unravel the apparent multiple strings of causation involved in Alzheimer’s Disease (AD) and similar neurodegenerative diseases of the brain.
The new research involving microtubule stabilisation, was performed in transgenic mice, meaning that results in human populations using such treatments may be quite different. The fact that both amyloid placques and tau tangles are seen in pathological brain specimens from AD patients suggests that more than one treatment approach may ultimately be required for many, if not most AD sufferers.
Cross-posted from Al Fin blog
Al Fin Longevity
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 1×10 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
Al Fin Longevity
Sleep Phases and Progression
Levels of adenosine triphosphate (ATP), the energy currency of cells, in rats increased in four key brain regions normally active during wakefulness. Shown here is the energy surge measured in the frontal cortex, a brain region associated with higher-level thinking. Credit: Courtesy, with permission: Dworak et al. The Journal of Neuroscience 2010.We spend roughly 1/3 of our lives in the state of sleep. Researchers are beginning to learn why we must do this, and are gleaning hints of possible technologies for bypassing at least part of the sleep imperative, and doing well on less sleep.
“For a long time, researchers have known that sleep deprivation results in increased levels of adenosine in the brain, and has this effect from fruit flies to mice to humans.” Abel said. “There is accumulating evidence that this adenosine is really the source of a number of the deficits and impact of sleep deprivation, including memory loss and attention deficits. One thing that underscores that evidence is that caffeine is a drug that blocks the effects of adenosine, so we sometimes refer to this as ‘the Starbucks experiment.’”
Abel’s research actually involved two parallel experiments on sleep-deprived mice, designed to test adenosine’s involvement in memory impairment in different ways.
One experiment involved genetically engineered mice. These mice were missing a gene involved in the production of glial transmitters, chemicals signals that originate from glia, the brain cells that support the function of neurons. Without these gliatransmitters, the engineered mice could not produce the adenosine the researchers believed might cause the cognitive effects associated sleep deprivation.
The other experiment involved a pharmacological approach. The researchers grafted a pump into the brains of mice that hadn’t been genetically engineered; the pump delivered a drug that blocked a particular adenosine receptor in the hippocampus. If the receptor was indeed involved in memory impairment, sleep-deprived mice would behave as if the additional adenosine in their brains was not there.
…To see whether these mice showed the effects of sleep deprivation, the researchers used an object recognition test. On the first day, mice were placed in a box with two objects and were allowed to explore them while being videotaped. That night, the researchers woke some of the mice halfway through their normal 12-hour sleep schedule.
On the second day, the mice were placed back in the box, where one of the two objects had been moved, and were once again videotaped as they explored to see how they reacted to the change.
“Mice would normally explore that moved object more than other objects, but, with sleep deprivation, they don’t,” Abel said. “They literally don’t know where things are around them.”
Both sets of treated mice explored the moved object as if they had received a full night’s sleep.
“These mice don’t realize they’re sleep-deprived,” Abel said.
Abel and his colleagues also examined the hippocampi of the mice, using electrical current to measure their synaptic plasticity, or how strong and resilient their memory-forming synapses were. The pharmacologically and genetically protected mice showed greater synaptic plasticity after being sleep deprived than the untreated group.
Combined, the two experiments cover both halves of the chemical pathway involved in sleep deprivation. The genetic engineering experiment shows where the adenosine comes from: glia’s release of adenosine triphosphate, or ATP, the chemical by which cells transfer energy to one another. And the pharmacological experiment shows where the adenosine goes: the A1 receptor in the hippocampus. _MedicalXpress
Abel’s is a sophisticated experiment which covers a lot of possiblities. Combining the findings of this experiment with findings of previous experiments gives one a fuller picture of what is going on.
The brain has evolved certain activity in N2 sleep (sleep spindles) which apparently promotes the production of ATP from adenosine and phosphate groups. As ATP levels rise in N2 sleep, adenosine levels drop. So the sound sleeper receives both the benefits of higher ATP energy levels and the improved learning that results from lower hippocampal free adenosine levels.
More on sleep spindles (PDF)
Adenosine is a potent pharmacological agent, powerfully affecting heart rhythms. It also affects central nervous system activity in a largely inhibitory function, and also exhibits anti-inflammatory effects.
Adenosine and deep brain stimulation (DBS)
Why Do We Sleep? A brief look at stages of sleep, and possible benefits of sleep.
Cross posted to Al Fin, the Next Level
How could we manage on less sleep? The fastest route to achieving high-functioning sleep reduction would seem to involve electromagnetic brain stimulation or inhibition over particular brain areas at specific pulse frequencies. The aim would be to reduce adenosine levels — and increase ATP levels — in specific areas of the brain including the hippocampus.
Pharmacological methods for blocking adenosine’s effect, such as used in the experimental mice in the study above, offer another possiblity — although a time delay before approval for a new drug of at least 10 years is to be expected.
Genetic techniques for modifying adenosine production or re-uptake and ATP synthesis, are another likely approach — eventually. At the present time, genetic (and epigenetic) treatment methods are far too primitive and clumsy to risk for such an objective as sleep reduction, for most people.
Other neuromolecules are likely involved in this puzzle, but at least this information offers a place to start.
Al Fin Longevity
