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Mars Base

Study unravels central mystery of Alzheimer's disease - 0 views

medicalxpress.com/...mystery-alzheimer-disease.html

scibyte90 Alzheimer

shared by Mars Base on 11 Apr 13 - No Cached
  • Until recently, Polleux's laboratory has been focused not on Alzheimer's research but on the normal development and growth of neurons
  • In 2011
  • reported that AMPK overactivation by metformin, among other compounds, in animal models impaired the ability of neurons to grow output stalks, or axons
  • ...25 more annotations...
  • Around the same time, separate research groups found clues that AMPK might also have a role in Alzheimer's disease
  • One group reported that AMPK can be activated in neurons by amyloid beta, which in turn can cause a modification of the protein tau in a process known as phosphorylation
  • a postdoctoral research associate
  • began by confirming that amyloid beta, in the small-aggregate ("oligomer") form that is toxic to synapses, does indeed strongly activate AMPK
  • amyloid beta oligomers stimulate certain neuronal receptors, which in turn causes an influx of calcium ions into the neurons
  • that this calcium influx triggers the activation of an enzyme called CAMKK2, which appears to be the main activator of AMPK in neurons
  • AMPK overactivation in neurons is the essential reason for amyloid beta's synapse-harming effect
  • neurons' dendritic spines—the rootlike, synapse-bearing input stalks that receive signals from other neurons
  • scientists showed that amyloid beta oligomers can't cause this dendritic spine loss unless AMPK overactivation occurs—and indeed AMPK overactivation on its own can cause the spine loss
  • the team used J20 mice, which are genetically engineered to overproduce mutant amyloid beta
  • when we blocked the activity of CAMKK2 or AMPK in these neurons, we completely prevented the spine loss
  • Recent studies have shown that amyloid beta's toxicity to dendritic spines depends largely on the presence of tau, but just how the two Alzheimer's proteins interact has been unclear
  • their colleagues are now following up with further experiments to determine what other toxic processes, such as excessive autophagy, are promoted by AMPK overactivation and might also contribute to the long-term aspects of Alzheimer's disease progression
  • also interested in the long-term effects of blocking AMPK overactivation in the J20 mouse model as well as in other mouse models of Alzheimer's disease, which normally develop cognitive deficits at later stages
  • the pharmaceuticals industry who are potentially interested in targeting either CAMKK2 or AMPK
  • show that brain damage in Alzheimer's disease is linked to the overactivation of an enzyme called AMPK
  • Researchers have known for years that people in the earliest stages of Alzheimer's disease begin to lose synapses in certain memory-related brain areas
  • findings, reported in the April
  • Small aggregates of the protein amyloid beta can cause this
  • but how they do so has been a mystery
  • Tangles of tau with multiple phosphorylations ("hyperphosphorylated" tau) are known to accumulate in neurons in affected brain areas in Alzheimer
  • investigate further, to determine whether the reported interactions of AMPK with amyloid beta and tau can in fact cause the damage seen in the brains of Alzheimer's patients
  • In addition
  • findings suggest the need for further safety studies on an existing drug, metformin.
  • , a popular treatment for Type 2 Diabetes, causes AMPK activation.
Mars Base

Early sign of Alzheimer's reversed in lab - 0 views

medicalxpress.com/...ly-alzheimer-reversed-lab.html

scibyte24

shared by Mars Base on 01 Dec 11 - No Cached
  • One of the earliest known impairments caused by Alzheimer's disease - loss of sense of smell – can be restored by removing a plaque-forming protein in a mouse model of the disease
  • study confirms that the protein, called amyloid beta, causes the loss
  • we can use the sense of smell to determine if someone may get Alzheimer's disease, and use changes in sense of smell to begin treatments, instead of waiting until someone has issues learning and remembering
  • ...12 more annotations...
  • We can also use smell to see if therapies are working
  • Smell loss can be caused by a number of ailments
  • since the 1970s, it has been identified as an early sign of this disease
  • There is currently no effective treatment or cure for the disease
  • They found that just a tiny amount of amyloid beta – too little to be seen on today's brain scans - causes smell loss in mouse models
  • Amyloid beta plaque accumulated first in parts of the brain associated with smell, well before accumulating in areas associated with cognition and coordination
  • Despite spending more time sniffing, the mice failed to remember smells and became incapable of telling the difference between odors
  • While losses in the olfactory system occurred, the rest of the mouse model brain, including the hippocampus, which is a center for memory, continued to act normally early in the disease stage
  • Mice were given a synthetic liver x-receptor agonist, a drug that clears amyloid beta from the brain
  • After two weeks on the drug, the mice could process smells normally
  • After withdrawal of the drug for one week, impairments returned
  • team are now following-up on these discoveries to determine how amyloid spreads throughout the brain, to learn methods to slow disease progression
Mars Base

Scientists discover previously unknown cleaning system in brain - 0 views

medicalxpress.com/...-previously-unknown-brain.html

medical

shared by Mars Base on 16 Aug 12 - No Cached
  • A previously unrecognized system that drains waste from the brain at a rapid clip has been discovered by neuroscientists at the University of Rochester Medical Center
  • highly organized system acts like a series of pipes that piggyback on the brain's blood vessels, sort of a shadow plumbing system that seems to serve much the same function in the brain as the lymph system does in the rest of the body – to drain away waste products
  • hopeful that these findings have implications for many conditions that involve the brain, such as traumatic brain injury, Alzheimer's disease, stroke, and Parkinson's disease
  • ...11 more annotations...
  • made the findings in mice, whose brains are remarkably similar to the human brain
  • Scientists have known that cerebrospinal fluid or CSF plays an important role cleansing brain tissue, carrying away waste products and carrying nutrients to brain tissue through a process known as diffusion
  • The newly discovered system circulates CSF to every corner of the brain much more efficiently, through what scientists call bulk flow or convection
  • It's as if the brain has two garbage haulers – a slow one that we've known about, and a fast one that we've just met
  • How has this system eluded the notice of scientists up to now
  • the system operates only when it's intact and operating in the living brain, making it very difficult to study
  • study the living, whole brain, the team used a technology known as two-photon microscopy, which allows scientists to look at the flow of blood, CSF and other substances in the brain of a living animal
  • If the glymphatic system fails to cleanse the brain as it is meant to, either as a consequence of normal aging, or in response to brain injury, waste may begin to accumulate in the brain. This may be what is happening with amyloid deposits in Alzheimer's disease
  • Perhaps increasing the activity of the glymphatic system might help prevent amyloid deposition from building up or could offer a new way to clean out buildups of the material in established Alzheimer's disease
  • took an in-depth look at amyloid beta
  • found that more than half the amyloid removed from the brain of a mouse under normal conditions is removed via the glymphatic system
Mars Base

New drug could treat Alzheimer's, multiple sclerosis and brain injury - 0 views

medicalxpress.com/...-multiple-sclerosis-brain.html

Alzheimer MultipleSclerosis GrabBag

shared by Mars Base on 25 Jul 12 - No Cached
  • A new class of drug
  • shows early promise of being a one-size-fits-all therapy for Alzheimer's disease, Parkinson's disease, multiple sclerosis and traumatic brain injury by reducing inflammation in the brain
  • The drugs
  • ...22 more annotations...
  • target a particular type of brain inflammation
  • brain inflammation, also called neuroinflammation, is increasingly believed to play a major role in the progressive damage characteristic of these chronic diseases and brain injuries.
  • offers an entirely different therapeutic approach to Alzheimer's than current ones being tested to prevent the development of beta amyloid plaques in the brain
  • The plaques are an indicator of the disease but not a proven cause
  • given to a mouse genetically engineered to develop Alzheimer's, it prevents the development of the full-blown disease
  • identifies the optimal therapeutic time window for administering the drug, which is taken orally and easily crosses the blood-brain barrier.
  • In previous animal studies, the same drug reduced the neurological damage caused by closed-head traumatic brain injury and inhibited the development of a multiple sclerosis-like disease. In these diseases as well as in Alzheimer's, the studies show the therapy time window is critical
  • work by preventing the damaging overproduction of brain proteins called proinflammatory cytokines
  • Scientists now believe overproduction of these proteins contributes to the development of many degenerative neurological diseases
  • When too many of the cytokines are produced, the synapses of the brain begin to misfire
  • mouse model of Alzheimer's received MW151 three times a week starting at six months of age, right at the time the proinflammatory cytokines began to rise. This would be the comparable stage when a human patient would begin to experience mild cognitive impairment
  • drug protected against the damage associated with learning and memory impairment
  • before Alzheimer's memory changes are at a late stage may be a promising future approach to therapy
  • In M.S., overproduction of the proinflammatory cytokines damage the central nervous system and the brain
  • proteins directly or indirectly destroy the insulation or coverings of the nerve cells that transmit signals down the spinal cord
  • insulation is stripped, messages aren't properly conducted down the spinal cord
  • When mice that were induced to develop an M.S.-like disease received MW151 orally, they did not develop disease as severe.
  • After a traumatic brain injury, the glia cells in the brain become hyperactive and release a continuous cascade of proinflammatory cytokines
  • As a result of this hyperactivity, researchers believe the brain is more susceptible to serious damage following a second neurological injury.
  • when MW151 is given during an early therapeutic window three to six hours after the injury, it blocks glial activation and prevents the flood of proinflammatory cytokines after a traumatic brain injury
  • early on after traumatic brain injury or a even a stroke, you could possibly prevent the long-term complications of that injury including the risk of seizures, cognitive impairment and, perhaps, mental health issues
  • Stroke also causes inflammation in the brain that may also be linked to long-term complications including epilepsy and cognitive deficits
Mars Base

New drug reverses loss of brain connections in Alzheimer's disease - 0 views

medicalxpress.com/...rses-loss-brain-alzheimer.html

scibyte99 Alzheimer

shared by Mars Base on 18 Jun 13 - No Cached
  • The first experimental drug to boost brain synapses lost in Alzheimer's disease
  • combines two FDA-approved medicines to stop the destructive cascade of changes in the brain that destroys the connections between neurons, leading to memory loss and cognitive decline.
  • The decade-long study
  • ...21 more annotations...
  • shows that NitroMemantine can restore synapses, representing the connections between nerve cells (neurons) that have been lost during the progression of Alzheimer's in the brain
  • These findings actually mean that you might be able to intercede not only early but also a bit later
  • Alzheimer's patient may be able to have synaptic connections restored even with plaques and tangles already in his or her brain.
  • study, conducted in animal models as well as brain cells derived from human stem cells,
  • team mapped the pathway that leads to synaptic damage in Alzheimer
  • found that amyloid beta peptides, which were once thought to injure synapses directly
  • actually induce the release of excessive amounts of the neurotransmitter glutamate from brain cells called astrocytes that are located adjacent to the nerve cells.
  • Normal levels of glutamate promote memory and learning, but excessive levels are harmful
  • Alzheimer's disease, excessive glutamate activates extrasynaptic receptors, designated eNMDA receptors
  • which get hyperactivated and in turn lead to synaptic loss
  • lab had previously discovered how a drug called memantine can be targeted to eNMDA receptors to slow the hyperactivity seen in Alzheimer's.
  • memantine's effectiveness has been limited.
  • memantine—a positively charged molecule—is repelled by a similar charge inside diseased neurons
  • memantine gets repelled from its intended eNMDA receptor target on the neuronal surface.
  • FDA approval of memantine in 2003
  • a fragment of the molecule nitroglycerin—a second FDA-approved drug commonly used to treat episodes of chest pain or angina in people with coronary heart disease—could bind to another site that the Lipton group discovered on NMDA receptors.
  • memantine rather selectively binds to eNMDA receptors, it also functions to target nitroglycerin to the receptor
  • by combining the two, Lipton's lab created a new, dual-function drug
  • researchers developed 37 derivatives of the combined drug before they found one that worked
  • By shutting down hyperactive eNMDA receptors on diseased neurons, NitroMemantine restores synapses between those neurons
  • NitroMemantine brings the number of synapses all the way back to normal within a few months of treatment in mouse models of Alzheimer's disease. In fact, the new drug really starts to work within hours
Mars Base

Alzheimer's: A Ray of Hope? Just Perhaps Maybe | Talking back, Scientific American Blog... - 0 views

blogs.scientificamerican.com/...ray-of-hope-just-perhaps-maybe

scibyte55 Alzheimer

shared by Mars Base on 19 Jul 12 - No Cached
  • pharmaceutical company Baxter International reported
  • a drug that, if it works in larger clinical trials now under way, might actually stabilize patients and stop disease progression
  • Gammagard, or intravenous immunoglobulin, a soup of antibodies extracted from blood donors and already approved for some immune disorders, halted for three years  any decline in cognition and in the ability to perform everyday tasks for four patients who received  the highest dose
  • ...13 more annotations...
  • Four patients
  • may be nothing
  • for sure
  • the drug may falter and go by the wayside as it makes its way through the clinical trials pipeline
  • results still intrigued some in the research community
  • Results from late-stage clinical trials next year will show whether these four were patients who just happened to have plateaued for a while during their inevitable decline
  • initial findings are encouraging, they are extremely preliminary
  • Until the results of the larger double-blind Phase 3 results demonstrate a significant benefit, intravenous immunoglobulin’s role in the treatment of AD is unproven
  • If later trials succeed, the results would give credence to the idea that Alzheimer’s usual suspect—a toxic peptide called amyloid-beta—is, in fact, the major heavy in the neurodegeneration
  • positive Phase III trial next year will mean, though, that the real work lies ahead
  • The drug, not covered by insurers, is already used off-label to treat Alzheimer’s by some rich patients who can afford to shell out $50,000 a year from their own pockets
  • If one day insurers were to cover Gammagard, not enough supply would exist for the donor-based drug—and shortages would make life difficult for  patients already using it for immune conditions
  • promising outcome for the drug trial may serve more as a proof of principle
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