Tagged: Alzheimer’s

On your MARCKS. Get set. Go

 

An important aspect of developing better remedies for Parkinson’s involves determining when and where the condition starts in the brain. What is the underlying mechanism that kicks things off and can it be therapeutically targetted?

Recently, researchers from Japan have suggested that a protein called Myristoylated alanine-rich C-kinase substrate (or simply MARCKS) may be a potentially important player in the very early stages of Parkinson’s (and other neurodegenerative conditions).

Specifically, they have found that MARCKS is present before many of the other pathological hallmarks of Parkinson’s (such as Lewy bodies) even appear. But what does this mean? And what can we do with this information?

In today’s post, we will look at what MARCKS is, what new research suggests, and how the research community are attempting to target this protein.

 


Where does it all begin? Source: Cafi

One of the most interesting people I met during my time doing Parkinson’s assessment clinics was an ex-fire forensic investigator.

We would generally start each PD assessment session with a “brief history” of life and employment – it is a nice ice breaker to the appointment, helped to relax the individual by focusing on a familiar topic, and it could provide an indication of potential issues to consider in the context of Parkinson’s – such as job related stress or exposure to other potential risk factors (eg. pesticides, etc).

Source: Assessment

But so fascinated was I with the past emplyoment of the ex-fire forensic investigator gentleman that the “brief history” was anything but brief.

We had a long conversation.

One aspect of fire forensics that particularly fascinated me was the way he could walk into a recently burned down property, and he could “read the story backwards” to identify the root cause of the fire.

He could start anywhere on a burnt out property and find his way back to the source (and also determine if the fire was accidental or deliberate).

Where did it all start? Source: Morestina

I marvelled at this idea.

And I can remember wondering “why can’t we do that with Parkinson’s?

Well, recently some Japanese researchers have had a crack at “reading the story backwards” and they found something rather interesting.

What did they find?

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From Alchemy to Alkahest

 

Numerous readers have asked about a curious new clinical trial being conducted by a biotech firm called ‘Alkahest’. The company has recently initiated a large (90 participants) Phase II study of their Parkinson’s-focused treatment called GRF6021.

This is an experimental, intravenously-administered treatment, which is derived from a components of blood.

In today’s post, we will discuss some of the research behind GRF6021, what this new clinical trial involves, and have a look at some other interesting Parkinson’s-related activities that Alkahest has ongoing.

 


Source: SFN

The Society of Neuroscience meeting is the largest annual research conference on brain relelated research, bringing approximately 40,000 neuroscientists together in October. At the Society of Neuroscience meeting in San Diego this year, however, there was considerable interest focused on several presentations dealing with blood.

The first presentation was from a group of researchers at the University of California, San Francisco.

The research team – led by group leader Dr Saul Villeda – were presenting new data suggesting that circulating immune cells were most likely responsible for the age-related reduction in neurogenesis (formation of new neurons) that occurs in certain areas of the brain (Click here to read the abstract for this presentation). They reported that the aged hematopoietic (blood) system led to impaired neurogenesis. Their take-home-message: the older the blood system, the less new cells being produced by the brain.

Sounds interesting right?

Well, at the same time in another part of the conference a second group of researchers were presenting equally impressive data: They have zeroed in of a small fraction of normal, young blood that they believe has interesting properties, particularly in reversing the cognitive deficits associated with aging mice (Click here to read the abstract of this presentation).

Their research has even narrowed down to a specific protein, called C-C chemokine receptor type 3 (or CCR3), which when inhibited was found to improve cognitive function and decreased neuroinflammation in aged mice (Click here to read the abstract of the presentation).

The humble lab mouse. Source: Pinterest

But specifically for our interests here at the SoPD, these same researchers displayed data which demonstrated that treatment with a novel fraction of human plasma resulted in significant improvements in motor function, cell survival and neuroinflammation three weeks after treatment in multiple mouse models of Parkinson’s (Click here to read the abstract of the poster).

(PLEASE NOTE: The author of this blog was not present at the SFN meeting and is working solely with the abstracts provided)

This second group of scientists were from a company called Alkahest, and they have recently started a clinical trial for people with Parkinson’s based on these results. That trial has garnered quite a bit of interest in the Parkinson’s community.What do Alkahest do?

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Denali: Phase Ib clinical trial starts

 

Biotech firm Denali announced the dosing of the first person in their Phase Ib clinical study of their experimental treatment for Parkinson’s called DNL201.

DNL201 is an inhibitor of a Parkinson’s-associated protein called Leucine-rich repeat kinase 2 (LRRK2).

In Parkinson’s, there is evidence that LRRK2 is over activate, and by inhibiting LRRK2 Denali is hoping to slow the progression of Parkinson’s.

In today’s post, we will discuss what LRRK2 is, what evidence exists for DNL201, and what the new clinical trial will involve.

 


 

Founded in 2013, by a group of former Genentech executives, San Francisco-based Denali Therapeutics is a biotech company which is focused on developing novel therapies for people suffering from neurodegenerative diseases. Although they have product development programs for other condition (such as Amyotrophic Lateral Sclerosis and Alzheimer’s disease), Parkinson’s is their primary interest.

And their target for therapeutic effect?

The Parkinson’s-associated protein called Leucine-rich repeat kinase 2 (or LRRK2).

What is LRRK2?

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Wanted: EEF2K inhibitors

Nuclear factor erythroid 2–related factor 2 (or NRF2) is a protein in each of your cells that plays a major role in regulating resistance to stress. As a result of this function, NRF2 is also the target of a lot of research focused on neuroprotection.

A group of researchers from the University of British Columbia have recently published interesting findings that point towards to a biological pathway that could help us to better harness the beneficial effects of NRF2 in Parkinson’s.

In today’s post, we will discuss what NRF2 is, what the new research suggests, and how we could potentially make use of this new information.


GettyImages-548553969-56a134395f9b58b7d0bd00df

Rusting iron. Source: Thoughtco

In his book ‘A Red Herring Without Mustard‘, author Alan Bradley wrote:

Oxidation nibbles more slowly – more delicately, like a tortoise – at the world around us, without a flame, we call it rust and we sometimes scarcely notice as it goes about its business consuming everything from hairpins to whole civilizations

And he was right on the money.

Oxidation is the loss of electrons from a molecule, which in turn destabilises that particular molecule. It is a process that is going on all around us – even within us.

Iron rusting is the example that is usually used to explain oxidation. Rust is the oxidation of iron – in the presence of oxygen and water, iron molecules will lose electrons over time. And given enough time, this results in the complete break down of objects made of iron.

The combustion process of fire is another example, albeit a very rapid form of oxidation.

Oxidation is one half of a process called Redox – the other half being reduction (which involves the gaining of electrons).

The redox process. Source: Academic

Here is a video that explains the redox process:

Now it is important to understand, that oxidation also occurs in biology.

Molecules in your body go through the same process of losing electrons and becoming unstable. This chemical reaction leads to the production of what we call free radicals, which can then go on to damage cells.

What is a free radical?

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A tiny dot with an anti-Parkinson’s plot

Graphene is widely being believed to be one of the building blocks of the future. This revolutionary 2D material is being considered for all kinds of applications, including those of a medicinal nature.

This week researchers from the John Hopkins University School of Medicine and Seoul National University have published a report suggesting that graphene may also have applications for Parkinson’s.

The researchers found that exposing the Parkinson’s-associated protein, alpha synuclein, to graphene quantum dots not only prevented the protein from aggregating together into its toxic form, but also destroyed the mature toxic form of it.

A nano-sized silver bullet?

In today’s post, we will look at what graphene quantum dots are, review the new Parkinson’s-related results, and discuss what happens next for this new technology.


Prof Andre Geim and Prof Konstantin Novoselov. Source: Aerogelgraphene

They called them ‘Friday night experiments’.

Each week, two research scientists at the University of Manchester (UK) named Andre Geim and Konstantin Novoselov held sessions where they would conduct experiments that had little or nothing to do with their actual research.

These activities were simply an exercise in genuine curiosity.

And on one particular Friday in 2004, the two scientists conducted one of the simplest experiments that they had ever attempted – but it was one which would change the world: They took some sticky tape and applied it to a lump of graphite.

What is graphite?

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I’ll have the fish please

We have previously discussed the importance of the right foods for people with Parkinson’s on this blog – Click here for a good example.

Recently, new data from researchers in Sweden points towards the benefits of a specific component of fish in particular.

It is a protein called β-parvalbumin, which has some very interesting properties.

In today’s post, we discuss what beta-parvalbumin is, review the new research findings, and consider how this new information could be applied to Parkinson’s.


A very old jaw bone. Source: Phys

In 2003, researchers found 34 bone fragments belonging to a single individual in a cave near Tianyuan, close to Beijing (China).

But it was not the beginning of a potential murder investigation.

No, no.

This was the start of something far more interesting.

Naming the individual “Tianyuan man”, the researchers have subsequently found that “many present-day Asians and Native Americans” are genetically related to this individual. His bones represented one of the oldest set of modern human remains ever found in the eastern Eurasia region.

Tianyuan caves. Source: Sciencemag

But beyond the enormous family tree, when researchers further explored specific details about his jaw bone (or lower mandible as it is called) they found something else that was very interesting about Tianyuan man:


Title: Stable isotope dietary analysis of the Tianyuan 1 early modern human.
Authors: Hu Y, Shang H, Tong H, Nehlich O, Liu W, Zhao C, Yu J, Wang C, Trinkaus E, Richards MP.
Journal: Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):10971-4.
PMID: 19581579                     (This research article is OPEN ACCESS if you would like to read it)

In this study, the investigators analysed the carbon and nitrogen isotopes found within bone collagen samples taken from the jaw bone of Tianyuan man. In humans, the carbon and nitrogen isotope values indicate the sources of dietary protein over many years of life.

The researchers found that a substantial portion of Tianyuan man’s diet 40,000 years ago came from freshwater fish.

Interesting preamble, but what does this have to do with Parkinson’s?

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Reduce your RAGE as you AGE

An Advanced Glycation Endproduct (or AGE) is a protein or lipid that has become glycated.

Glycation is a haphazard process that impairs the normal functioning of molecules. It occurs as a result of exposure to high amounts of sugar. These AGEs are present at above average levels in people with diabetes and various ageing-related disorders, including neurodegenerative conditionsAGEs have been shown to trigger signalling pathways within cells that are associated with both oxidative stress and inflammation, but also cell death.

RAGE (or receptor of AGEs) is a molecule in a cell membrane that becomes activated when it interacts with various AGEs. And this interaction mediates AGE-associated toxicity issues. Recently researchers found that that neurons carrying the Parkinson’s associated LRRK2 G2019S genetic variant are more sensitive to AGEs than neurons without the genetic variant. 

In today’s post we will look at what AGE and RAGE are, review the new LRRK2 research, and discuss how blocking RAGE could represent a future therapeutic approach for treating Parkinson’s.


The wonder of ageing. Source: Club-cleo

NOTE: Be warned, the reading of this post may get a bit confusing. We are going to be discussing ageing (as in the body getting old) as well as AGEing (the haphazard process processing of glycation). For better clarification, lower caps ‘age’ will refer to getting old, while capitalised ‘AGE’ will deal with that glycation process. I hope this helps.


Ageing means different things to different people.

For some people ageing means more years to add to your life and less activity. For others it means more medication and less hair. More wrinkles and less independence; more arthritis and less dignity; More candles, and less respect from that unruly younger generation; More… what’s that word I’m thinking of? (forgetfulness)… and what were we actually talking about?

Wisdom is supposed to come with age, but as the comedian/entertainer George Carlin once said “Age is a hell of a price to pay for wisdom”. I have to say though, that if I had ever met Mr Carlin, I would have suggested to him that I’m feeling rather ripped off!

George Carlin. Source: Thethornycroftdiatribe

Whether we like it or not, from the moment you are born, ageing is an inevitable part of our life. But this has not stopped some adventurous scientific souls from trying to understand the process, and even try to alter it in an attempt to help humans live longer.

Regardless of whether you agree with the idea of humans living longer than their specified use-by-date, some of this ageing-related research could have tremendous benefits for neurodegenerative conditions, like Parkinson’s.

What do we know about the biology of ageing?

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Trazodo or Trazodon’t?

“Repurposing” in medicine refers to taking drugs that are already approved for the treatment of one condition and testing them to see if they are safe and effective in treating other diseases. Given that these clinically available drugs have already been shown to be safe in humans, repurposing represents a method of rapidly acquiring new potential therapeutics for a particular condition. 

The antidepressant, Trazodone, has recently been proposed for repurposing to neurodegenerative conditions, such as Parkinson’s. 

In today’s post we will look at what Trazodone is, why it is being considered for repurposing, and we will review the results of a new primate study that suggests it may not be ideal for the task.


Opinions. Everyone has them. Source: Creativereview

I am regularly asked by readers to give an opinion on specific drugs and supplements.

And I usually cut and paste in my standard response: I can not answer these sorts of questions as I am just a research scientist not a clinician; and even if I was a clinician, it would be unethical for me to comment as I have no idea of your medical history.

In many of these cases, there simply isn’t much proof that the drug/supplement has any effect in Parkinson’s, so it is hard to provide any kind of “opinion”. But even if there was proof, I don’t like to give opinions.

Eleven out of every ten opinions are usually wrong (except in the head of the beholder) so why would my opinion be any better? And each individual is so different, why would one particular drug/supplement work the same for everyone?

In offering an answer to “my opinion” questions, I prefer to stick to the “Just the facts, ma’am” approach and I focus solely on the research evidence that we have available (Useless pub quiz fact: this catchphrase “Just the facts, ma’am” is often credited to Detective Joe Friday from the TV series Dragnet, and yet he never actually said it during any episode! – Source).

Detective Joe Friday. Source: Wikipedia

Now, having said all of that, there is one drug in particularly that is a regular topic of inquiry (literally, not a week goes by without someone asking about): an antidepressant called Trazodone.

What is Trazodone?

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When the zombies are all in your head

In your brain there are different types of cells.

Firstly there are the neurons (the prima donnas that we believe do most of the communication of information). Next there are the microglia cells, which act as the first and main line of active immune defence in the brain. There are also oligodendrocyte, that wrap protective sheets around the branches of the neurons and help them to pass signals.

And then there are astrocytes.

These are the ‘helper cells’ which maintain a comfortable environment for the neurons and aid them in their task. Recently, researchers in California reported an curious observation in the Parkinsonian brain: some astrocytes have entered an altered ‘zombie’-like state. And this might not be such a good thing.

In today’s post, we’ll review the research and discuss what it could mean – if independently replicated – for the Parkinson’s community.


Zombies. Source: wallpapersbrowse

I don’t understand the current fascination with zombies.

There are books, movies, television shows, video games. All dealing with the popular idea of dead bodies wandering the Earth terrifying people. But why the fascination? Why does this idea have such appeal to a wide portion of the populous?

I just don’t get it.

Even more of a mystery, however, is where the modern idea of the ‘zombie’ actually came from originally.

You see, no one really knows.

Huh? What do you mean?

Some people believe that the word ‘zombie’ is derived from West African languages – ndzumbi means ‘corpse’ in the Mitsogo language of Gabon, and nzambi means the ‘spirit of a dead person’ in the Kongo language. But how did a word from the African continent become embedded in our psyche?

Others associate the idea of a zombie with Haitian slaves in the 1700s who believed that dying would let them return back to lan guinée (African Guinea) in a kind of afterlife. But apparently that freedom did not apply to situations of suicide. Rather, those who took their own life would be condemned to walk the Hispaniola plantations for eternity as an undead slave. Perhaps this was the starting point for the ‘zombie’.

More recently the word ‘zonbi’ (not a typo) appeared in the Louisiana Creole and the Haitian Creole and represented a person who is killed and was then brought to life without speech or free will.

Delightful stuff for the start of a post on Parkinson’s research, huh?

But we’re going somewhere with this.

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EDITORIAL: That Pfizer news

On Saturday 7th January, 2018, one of the world’s largest pharmaceutical companies – Pfizer – announced that it was abandoning research efforts focused on finding new drugs for Alzheimer’s and Parkinson’s. 

Naturally, the Parkinson’s and Alzheimer’s communities reacted with disappointment to the news, viewing it as a demoralising tragedy. And there was genuine concern that other pharmaceutical companies would follow suit in the wake of this decision.

Those fears, however, are unfounded.

In today’s post we will look at some of the reasons underlying Pfizer’s decision, why our approach to failure is wrong, why Pfizer will definitely be back, and what the Parkinson’s community can do about it all.


Photo by David Kovalenko on Unsplash

1. Our approach to failure

I am currently reading “Black box thinking: The Surprising Truth About Success“. It is a really interesting book by journalist Matthew Syed that investigates how we approach to failure.

Matthew Syed. Source: Amazon

In the first chapter of his book, Syed makes comparisons between the way the aviation industry and the medical profession approach failure, pointing out the processes that follow situations when a disasters occur. In the aviation industry, when any event occurs there is a major investigative process that starts with the recovery of the black boxes. The aviation industry uses this system of investigation to learn from every single incident. It makes the information available to all and this helps with re-thinking everything from cockpit ergonomics and design to air traffic controller procedures. Even the airline companies are keen to be seen to be involved in this process of investigation. Failure, while unfortunate, is not shameful or stigmatising, but rather embraced and enlightening. 

In addition, Syed points out that when an airline pilot sits down in his/her cockpit, their neck is also on the line if something goes wrong. Thus, it is in their best interest that the flight should be successful. And this is another reason why the aviation industry takes the reporting of failure so seriously. Everyone benefits from learning from previous situations. And all of this comes together with the observation that 2017 was the safest year on record for flying (based on deaths/flights – Source).

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