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New Thinking on Alzheimer’s: Time for a Paradigm Shift?

By Shlomo Maital

Scientific breakthroughs come from iconoclastic researchers who are not afraid to smash consensus paradigms. Take, for instance, Prof. Michal Schwarz, of Israel’s Weizmann Institute. Here is what she told this week’s Haaretz (Hebrew) reporter:

           The puzzle I pieced together is correct, and now I see the whole picture – how my research approach,  for years against the consensus, has become one of the central focal points for research on all degenerative (neural) diseases.

     The paradigm shift Schwarz has helped bring about is simple.   Many researchers follow the “I dropped a coin” model – they look for it under the corner streetlight, instead of in dark corners, where it fell, because…. “that’s where the light is”.   Alzheimer’s? Gooey proteins gumming up the brain and causing death?   Look for cures that eliminate or prevent the protein directly, in the brain.  Under the light.

       But Schwarz?     Let’s help the body’s own anti-immune system, outside the brain, fight those plaque accumulations that damage the brain. Last year the Daily Telegraph quoted Dr. Doug Brown, a leading Alzheimer’s researcher: “Repurposing drugs that already work for other conditions could provide us with a shortcut to new dementia treatments, and is a key aspect of our Drug Discovery programme.”  

         Here ‘s how the Daily Telegraph described Schwarz’s paradigm shift, in 2016:   “The drugs, known as PD-1 blockers, effectively prevent the immune system from switching off, allowing a continuous cascade of soldier cells to fight disease and clear out damage in the body. In the case of Alzheimer’s disease sticky amyloid plaques build up which stop brain cells communicating with each other. But when mice, engineered to have Alzheimer’s symptoms, were given injections of the drug the amount of amyloid in their brains halved, and the animals were able to complete a maze task in the same time as control mice.  Last year the first PD-1 blocker drug Keytruda was approved for use on the NHS by the National Institute for Health and Care Excellence so it is already known to be a safe treatment.

        “Lead author Prof Michal Schwartz of the Weizmann Institute of Science, Rehovot, Israel, said that in Alzheimer’s a weakened immune system could be preventing the body from repairing itself.    “We are extremely excited about our new study, we believe it is a game changer both conceptually and therapeutically,” she said.

      Her research was published in the leading journal Nature Medicine.

       Prof. Schwarz added: (in Hebrew):   “In contrast to veteran old-time researchers, students have no history of believing dogma (existing paradigms)…they are fresh ears and eyes, without preconceptions. They were especially excited, with me, at our results, and joined my research and contributed to moving it forward, and some of them are continuing in my wake.”

         As a (very) senior citizen, I have deep interest in breakthrough research on Alzheimer’s – half of those over 85 have it, at least early versions.   Congratulations to Prof. Schwarz for becoming a woman scientist and for leading a paradigm shift that may help millions – including those in countries that despise Israel.

 

Hope for Alzheimer’s Cure?

By Shlomo Maital

michaelson

Prof. Dan Michaelson

My family physician recently told me that about half of the elderly aged 85 and over have Alzheimer’s.   That should make Alzheimer’s a top priority for research money. But it is far from it.

Today’s Hebrew daily Maariv reports on a major breakthrough. Tel Aviv U. Prof. Dan Michaelson, along with his doctoral student Anat Bam-Cogan, have found a drug that can combat Alzheimer’s in mice. Here is the story:

     There are apparently quite a few ‘varieties’ of Alzheimer’s, just as there are types of cancer. Michaelson notes that 413 clinical trials, that tested 244 anti-Alzheimer’s drugs over the past 13 years, all failed!   Why? Maybe because Alzheimer’s is many diseases, not just one, he reasoned.

     Michaelson decided to tackle one type, related to specific genes ApoE3 and ApoE4.   Lab mice that have this defective gene develop Alzheimer’s. Michaelson tested the theory that the key protein that the defective ApoE4 gene makes fails to attach itself to fat cells properly, leading to the Alzheimer “plaque”. He contacted a biotech company Artery, and got from it a protein (peptide) that helps ‘stick’ fat cells to the protein. And it worked.   The peptide fixed the Alzheimer’s mice’s   cognitive problems and repaired the plaque in their brains.

     This is still a very long way from a drug that will help, or even cure, Alzheimer’s in humans. But it is a big step in the right direction.   We await more news from Dr. Michaelson, with hope.

Alzheimer’s Breakthrough?

By Shlomo Maital

Alzheimer plaque

   Alzheimer’s Disease causes some 70 per cent of all dementia. In terms of the numbers who suffer from it, the WHO (World Health Organization) estimates that in absolute numbers 26.6 million, with a huge range of 11.4–59.4 million,   were afflicted by AD, in the world,   and, most significant,   the prevalence rate would triple and the absolute number would quadruple by 2050.  So it would not be an exaggeration to call Alzheimer’s an epidemic.

     According to Lisa Desjardins, PBS News Hour: More than five million Americans live with the degenerative brain disease that robs people of their memory. It is the sixth leading cause of death in the U.S     Yet Alzheimer’s research is seriously underfunded. America’s National Cancer Institutes alone get some $5 billion a year. On pure economic grounds, a small fraction of that sum could be better invested in the causes of dementia. Few people today have been untouched by it.

     New research led by Harvard scientists brings hope that the cause of Alzheimer’s, still unknown, will soon be unraveled:

     “….a study led by Harvard University researchers and published this week in the journal “Science Translational Medicine” suggests that Alzheimer’s could stem from the brain’s past attempts to fight off infections.”

   According to Rob Moir, a researcher at Massachusetts General Hospital:   “Alzheimer’s disease and the neurodegeneration you see with it is thought to be caused by a little protein that forms this concrete like substance in your brain called amyloid. Amyloid, it turns out, is actually be an antimicrobial pit pod, that is to say it is a natural antibiotic that defends against infection in the brain, and if you get a virus or a bacteria that gets into the brain, it rises to do better with it and binds to it and then entraps it in these long fibers and eventually entombs it forever. And as they mount in number, eventually they start to be toxic to our own cells, and that leads to the neurodegeneration. So, that’s what I bet it does.”

     In short – Alzheimer’s is caused by amyloid plaque. Amyloid plaque in turn appears to be a result of the brain’s efforts to fight infection.  

     So what?   Notes Moir: “So if it does turn out to be an infection, there is a possibility of treating people before they get AD with vaccines, to target those particular bugs so that the pathogens don’t get a chance to infect the brain.”

     Let’s follow this research closely.   One day those 50 and over may get a vaccine, like those given to children, that protect their brains. As a senior citizen, few things scare me – but the idea that my brain may one day become scrambled is a major fear. The new Harvard research offers us hope.      

Can Down’s Syndrome Help Cure Alzheimer’s?

By Shlomo  Maital   

Down's

About eight years ago, the BBC reported this: 

   Scientists believe they have found a possible cause for mental impairment in Down’s syndrome.   They have identified a gene that, if over-produced, can cause some brain cells to stop working properly. The next step, say the US researchers in journal Neuron, is to find the mechanism for the process.  This, they say, could ultimately lead to finding a way to “turn down” the gene expression so mental decline might be stopped or even reversed.   People with Down’s syndrome have three copies of chromosome 21, instead of the normal two – this is called trisomy 21.  ….Many people with Down’s syndrome go on to develop dementia, similar to early-onset Alzheimer’s disease, by the age of 40.   In both Down’s syndrome and this form of Alzheimer’s, brain cells, or neurons, responsible for learning, memory and attention, wither and die.    Lead researcher Professor William Mobley, director of the Neuroscience Institute at Stanford University, said: “We’ve been interested in those neurons and why they get sick for some time.”

   Now, reports the BBC, in its excellent Science program,  Down’s syndrome persons are making major contributions to Alzheimer’s research.  Because Down’s syndrome individuals almost all develop the same type of ‘plaque’ dementia that afflicts Alzheimer’s sufferers, potential preventive drugs can be tested on Down’s syndrome persons well before they are 40, to see which drug actually works as a preventative, and whether such drugs really do prevent  the brain’s neurons from being gummed up by protein.

    It would be truly wonderful, if the Down’s syndrome persons willing to help scientists research Alzheimer’s  really do help find a drug that acts as a preventative.  Perhaps one day,  just as many of us take 75 mg. of aspirin daily as a stroke preventive,  we will take 75 mg. of a preventive drug daily– and the scourge of Alzheimer’s dementia will be defeated.     Once the protein plaque has taken hold, little can be done.  But clearly the direction for battling Alzheimer’s lies in preventing or forestalling it.   Let’s hope. 

     Thanks, Down’s people.  We love you.

 A Cure for Alzheimer’s?!

By Shlomo  Maital

         Alzheimer's

  I’ve been closely tracking research on Alzheimer’s, as researchers try to identify the cause,  diagnose the illness earlier and above all, find a possible cure.  The photograph above shows just how awful an illness it is, literally shrinking and damaging our brain, messing up neural connections with ugly protein tangles, and damaging our lives and those of our loved ones who care for sufferers.  By one estimate, there will be 75 million sufferers in 2030 and 135 million in 2050.  So, Alzheimer’s must become a top priority for medical research.

   On Wednesday a major new breakthrough by Harvard researchers was published in the journal Nature.  Here is how the Boston Globe described it:

 “… scientists identified a protein called REST that flips genes on and off and naturally increases during aging. REST, they found, represses genes involved in Alzheimer’s disease, and its levels are reduced in key brain areas of people diagnosed with Alzheimer’s or the mild cognitive impairment that precedes dementia.  In laboratory tests, REST protected brain cells from dying when exposed to a number of stresses, including the beta amyloid protein that accumulates in the brains of Alzheimer’s patients. … “What I love about this study, first and foremost, is it’s some good news for Alzheimer’s, and it connects that good news with an immediate therapeutic strategy,”Scripps Institute researcher Jeffrey  Kelly said. “There aren’t a lot of steps between this” and the development of experimental drugs.”

    The Harvard researchers took a new approach to Alzheimer’s, and found amazingly that there is a protein, created at birth, that can repress genes related to Alzheimer’s and other stresses.   Alzheimer’s patients seem to have too little of it.  The natural next step is to create a drug based on the REST protein.

    I think there is an important, hidden point to be made here.  Harvard Univ. has massive funds for research, flowing from its enormous endowment, and from other funding sources including those from industry.  Modern research is very expensive.  And availability of funds enables Harvard to attract and retain the very best research talent.   There are still Nobel winners out there who succeed with little money and poor equipment.  But that is becoming increasingly more difficult.   

 The Hunt for the Cause of Dementia: New Hope

By Shlomo  Maital

       prion           prions

  The latest issue of Scientific American (May 2013) describes vividly how scientists are on the trail to find the cause of Alzheimer’s and dementia, leading to hope for a cure.  We have known for years that Alzheimer’s is caused by clumps of proteins that lump together and destroy brain cells.  This has been known since 1906, when Alois Alzheimer identified the plaque linked to the disease.

         But why and how does this happen?

          A scientist, Stanley B. Prusiner, U. California San Francisco, found, in a series of brilliant experiments, what causes the brain to become like “Swiss cheese” in some diseases.   

      The culprit?  An innocuous protein, PrP, which when ‘misfolded’, causes other proteins to become mis-shaped, which in turn ‘infect’ other proteins, creating clumps that do great damage.  Prusiner called these protions ‘prions’ (proteinaceous infectious particles).  Of course, when he published his findings, scientists pooh-poohed them, doubting that a protein could act like a virus, infecting other proteins.  But in 1997 Prusiner won the Nobel Prize for his breakthrough.    

    Today we know prions cause “mad cow disease” (Creutzfeld-Jacob) and evidence grows that prions also cause Alzheimer’s and dementia.  Prions begin in one part of the brain, spread to other parts, eventually reaching the brain’s deepest reaches. 

     Now, what causes ‘prions’?   And is there a therapy that can halt their spread, or reverse it?   Some day, notes the Scientific American, “prion-like seeded protein aggregation may explain the origin of some of the most feared diseases of old age – and ..one day translate into treatments that alter the relentless progression of neurodegenerative illnesses”. 

   Let’s hope!

Blog entries written by Prof. Shlomo Maital

Shlomo Maital
April 2017
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