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Alzheimer’s Mystery Solved: How Amyloid Beta Forms in Brain Nerve Cells
https://scitechdaily.com ^ | OCTOBER 15, 2021 | By MASSACHUSETTS GENERAL HOSPITAL

Posted on 10/18/2021 7:48:32 AM PDT by Red Badger

Amyloid protein (orange) forms clumps among neurons (blue). Amyloid in the brain is one of the proteins associated with Alzheimer’s disease.

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In a major breakthrough, researchers at Massachusetts General Hospital (MGH) have discovered how amyloid beta — the neurotoxin believed to be at the root of Alzheimer’s disease (AD) — forms in axons and related structures that connect neurons in the brain, where it causes the most damage. Their findings, published in Cell Reports, could serve as a guidepost for developing new therapies to prevent the onset of this devastating neurological disease.

Among his many contributions to research on AD, Rudolph Tanzi, PhD, vice chair of Neurology and co-director of the McCance Center for Brain Health at MGH, led a team in 1986 that discovered the first Alzheimer’s disease gene, known as APP, which provides instructions for making amyloid protein precursor (APP). When this protein is cut (or cleaved) by enzymes — first, beta secretase, followed by gamma secretase — the byproduct is amyloid beta (sometimes shortened to Abeta). Large deposits of amyloid beta are believed to cause neurological destruction that results in AD. Amyloid beta formed in the brain’s axons and nerve endings causes the worst damage in AD by impairing communication between nerve cells (or neurons) in the brain. Researchers around the world have worked intensely to find ways to block the formation of amyloid beta by preventing cleavage by beta secretase and gamma secretase. However, these approaches have been hampered by safety issues.

Despite years of research, a major mystery has remained. “We knew that Abeta is made in the axons of the brain’s nerve cells, but we didn’t know how,” says Tanzi. He and his colleagues probed the question by studying the brains of mice, as well as with a research tool known as Alzheimer’s in a dish, a three-dimensional cell culture model of the disease created in 2014 by Tanzi and a colleague, Doo Yeon Kim, PhD. Earlier, in 2013, several other MGH researchers, including neurobiologist Dora Kovacs, PhD (who is married to Tanzi), and Raja Bhattacharyya, PhD, a member of Tanzi’s lab, showed that a form of APP that has undergone a process called palmitoylation (palAPP) gives rise to amyloid beta. That study indicated that, within the neuron, palAPP is transported in a fatty vesicle (or sac) known as a lipid raft. But there are many forms of lipid rafts. “So the question was, Which lipid rafts? And which ones are most relevant to the neuronal processes making up the neural networks of the brain?” says Tanzi.

The new investigation revealed that palAPP is stabilized and prepared for cleavage by beta secretase in special lipid rafts within the neuron known as mitochondria-associated endoplasmic reticulum membranes (MAMs). “We showed for the first time not only that the MAM is where palAPP is processed by beta secretase to make Abeta, but that this happens exclusively in axons and neuronal processes where Abeta does most of its damage,” says Bhattacharyya, lead author of the Cell Reports paper. This role for MAMs was previously unknown, though earlier research indicated that they are increased in number and activity in the brains of people with Alzheimer’s disease.

Next, the MGH team wanted to learn what happens when MAM levels and activity were intentionally altered. They showed for the first time that preventing assembly of MAMs, either with gene therapy or a drug that blocked a key protein called the sigma-1 receptor (S1R), dramatically decreased beta secretase cleavage of palAPP in axons and lowered Abeta production. Conversely, a drug that activated S1R triggered an increase in beta secretase cleavage of palAPP and increased production of amyloid beta in axons.

“Our results suggest that the sigma-1 receptor might be a viable therapeutic target for reducing Abeta production, specifically in axons,” says Tanzi. The study also lends support for a strategy already under investigation by Tanzi and his team, which is developing an experimental treatment that inhibits the palmitoylation of APP, the process that produces palAPP. It’s also known that another class of drugs that Kovacs is studying for preventing formation of amyloid beta, called ACAT inhibitors, works directly in MAMs. In the future, these and other interventions that thwart production of this most dangerous pool of axonal amyloid beta could be used in concert with early detection (through blood or imaging tests) to stop or slow the progression of AD.

Reference: “Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes” by Raja Bhattacharyya, Sophia E. Black, Madhura S. Lotlikar, Rebecca H. Fenn, Mehdi Jorfi, Dora M. Kovacs and Rudolph E. Tanzi, 18 May 2021, Cell Reports. DOI: 10.1016/j.celrep.2021.109134

Tanzi directs the Genetics and Aging Research Unit and co-directs the Henry and Allison McCance Center for Brain Health at MGH and is the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School (HMS). Bhattacharyya is also an instructor in Neurology at HMS.

This study was funded by grants from the National Institutes of Health and the Cure Alzheimer’s Fund.


TOPICS: Business/Economy; Health/Medicine; History; Society
KEYWORDS: alzheimers
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To: Red Badger

The right diet is pretty much protection against anything.

https://www.endalznow.org/news/research-shows-intermittent-fasting-may-prevent-alzheimers-disease


21 posted on 10/18/2021 8:21:17 AM PDT by erlayman
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To: Red Badger
Palmitoylation:
https://en.m.wikipedia.org/wiki/Palmitoylation

We need this process, but it appears to have become dysfunctional in Alzheimer's patients.

I come back, again and again, to the gradual, imperceptual changes a bad diet gives each of us. We may gain weight, or have additional issues inside, which we chalk up to “getting older,” when it was from multiple daily insults to our bodies which we did not overcome.

22 posted on 10/18/2021 8:23:30 AM PDT by ConservativeMind (Trump: Befuddling Democrats, Republicans, and the Media for the benefit of the US and all mankind.)
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To: PIF

“Any one care to put that medical science speak into simple English?”

Need a therapy to clean the gunk causing alzheimers off of the nerve endings.


23 posted on 10/18/2021 8:27:39 AM PDT by EQAndyBuzz (If you are vaccinated, you cannot get COVID from someone who is not vaccinated. Lighted up Karen!)
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To: EQAndyBuzz

So no real solution except some mysterious unnamed therapy, then?


24 posted on 10/18/2021 8:28:46 AM PDT by PIF (They came for me and mine ... now its your turn)
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To: Fightin Whitey

No argument there. My gma died from it, meaning my father is prime for it (he’s already exhibiting some memory issues).

I can’t tell you how frustrating it is to have both wife & father decline in health because they’re both too stubborn to listen to common sense (perhaps you know).


25 posted on 10/18/2021 8:31:28 AM PDT by logi_cal869 (-cynicus the "concern troll" a/o 10/03/2018 /!i!! &@$%&*(@ -)
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To: rarestia

hmmmm gene therapies

I hope this is for real and not a guise to put forth a new alzheimers vax that does nothing but degrade our t cells. Sorry but how can we trust after this covid debacle


26 posted on 10/18/2021 8:34:51 AM PDT by MomwithHope (Forever grateful to all our patriots, past, present and future.)
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To: Red Badger

I think they are doing their research in a fashion where they are trying to find a drug to patent. This is not really useful in my eyes. The reality is that Alzheimer’s is both genetically and habitually predictable. In other words you can figure out if you are at risk by looking at your siblings and other family members who are older. If they got it, you are more likely. In my family, every single female on my fathers side (a very large family) has died of Alzheimer’s. And secondly, you can look at those with fatty liver or diabetes 2. They are far more likely to get Alzheimer’s.

Alzheimer’s is a condition where avoidance is far better than a cure. The rate of Alzheimer’s has increased around the world as people start eating the Standard American Diet.

Given that, try not to contract fatty liver. That means staying away from Fructose, maybe alcohol and carbs. High Fructose Corn Starch was the most common way to ingest fructose for the past 40 years. Also fruit juices are very high in fructose.

These researchers are trying to let you eat wrong, get fat, continue your horribly unhealthy life style and take a pill that allows you to avoid Alzheimer’s but get your knees replaced and stay on numerous other pills designed to keep the unhealthy alive.


27 posted on 10/18/2021 8:35:23 AM PDT by poinq
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To: Red Badger

Oh that explains everything so simply even a cave man could understand!


28 posted on 10/18/2021 8:37:30 AM PDT by PIF (They came for me and mine ... now its your turn)
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To: PIF

Here’s the bottom line. The cell organelle that makes the protein that destroys neurons is controlled by an enzyme known as SIGMAR-1. Increase SIGMAR-1 blocks a critical receptor and the toxic protein is blocked from production. Healthy people produce SIGMAR-1 most of their life but it declines with age and severely declines with Alzheimer’s patients.

Currently the leading drug candidate that does exactly this is Anavex Lifesciences AVX-273 clinical trial.


29 posted on 10/18/2021 8:39:17 AM PDT by Dave Wright
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To: logi_cal869
We found a way to make money off of a drug which you must take to prevent the buildup of plaque, but you’re too dumb to understand that we’re taking advantage of you and withholding the information you need to prevent Alzheimer’s without our drugs.

Bingo.


30 posted on 10/18/2021 8:39:23 AM PDT by Cinnamontea
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To: PIF

Yeah. Start eating keto, and take it seriously. Every day.

No sugar, no carbs, no alcohol,

Get your weight within guidelines. Then lose 10% more.

Do your own research.

Eat and drink like an idiot and get Alzheimer’s, diabetes, heart disease, debilitating arthritis, kidney failure, etc, OR take your nutrition seriously and live 20 years longer, or more.

Jesus is Lord.


31 posted on 10/18/2021 8:39:31 AM PDT by Eccl 10:2 (Prov 3:5 --- "Trust in the Lord with all your heart, and lean not on your own understanwall ea ding")
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To: PIF

Big patented drug sales potential!


32 posted on 10/18/2021 8:39:39 AM PDT by 9YearLurker
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To: MomwithHope

Dr. Robert Malone has talked about the promise of mRNA therapies, but he’s also cautioned of its misapplication. He seems to veer heavily toward the misapplication side of the argument with the COVID stuff, but in time, it’s likely many of our medical therapies will make use of mRNA. There’s promise in it for cancers and things like Alzheimer’s, for sure.


33 posted on 10/18/2021 8:39:48 AM PDT by rarestia (Repeal the 17th Amendment and ratify Article the First to give the power back to the people!)
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To: PIF

I’ll put it in simple English for you. Wait . . . what was I saying?


34 posted on 10/18/2021 8:41:07 AM PDT by Maceman (People who vote Democrat sell their lives (and ours) to the government and their souls to the Devil.)
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To: poinq

“The reality is that Alzheimer’s is both genetically “

I think far yoo many times genetics get blamed when it is really families tend to eat similarly, for better or worse. I also believe Establishment Medicine pushes the genectics angle constantly so that the sheeple think many diseases are inevitable and you can do nothing but rely on them to save you.


35 posted on 10/18/2021 8:42:06 AM PDT by BiglyCommentary
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To: Red Badger

bookmark


36 posted on 10/18/2021 8:44:04 AM PDT by GOP Poet (Super cool you can change your tag line EVERYTIME you post!! :D. (Small things make me happy))
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To: PIF; Red Badger

“Any one care to put that medical science speak into simple English?”

They have identified the details of specific steps that occur, in producing the gunk that builds up in brains with Alzheimer’s. They also showed that by blocking one specific step, it would block production of that gunk.

However, that does not necessarily mean that blocking the gunk buildup, will prevent mental decline. Others have reduced the gunk, without reversing the mental decline.

In addition to the buildup of this gunk (Amyloid Beta), there is also a tangling that occurs among brain cells during Alzheimer’s, and inflammatory effects. It is possible that the gunk is just a secondary effect (symptom) of Alzheimer’s, and not the cause.

It was good, detailed research, that convincingly detailed some of the processes involved. So it is a significant step forward in understanding Alzheimer’s - but it is still a long way from a cure, and has not been shown to prevent it.


37 posted on 10/18/2021 8:45:18 AM PDT by BeauBo
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To: Sequoyah101
To cut to the chase;

Researchers want to figure out how to block a key protein called the sigma-1 receptor (S1R) from acting to create amaloid plaque in the brain.

----------------------------------------------------------------------------------------------------------------------- a bit longer version.

Researchers around the world have worked intensely to find ways to block the formation of amyloid beta by preventing cleavage by beta secretase and gamma secretase. However, these approaches have been hampered by safety issues.

a form of APP that has undergone a process called palmitoylation (palAPP) gives rise to amyloid beta.

The new investigation revealed that palAPP is stabilized and prepared for cleavage by beta secretase in special lipid rafts within the neuron known as mitochondria-associated endoplasmic reticulum membranes (MAMs). “We showed for the first time not only that the MAM is where palAPP is processed by beta secretase to make Abeta, but that this happens exclusively in axons and neuronal processes where Abeta does most of its damage,”

They showed for the first time that preventing assembly of MAMs, either with gene therapy or a drug that blocked a key protein called the sigma-1 receptor (S1R), dramatically decreased beta secretase cleavage of palAPP in axons and lowered Abeta production.

(and therefore Amloid plaque.)

Until they figure this out use Turmeric and fish oil!

38 posted on 10/18/2021 8:46:50 AM PDT by Pete from Shawnee Mission ( )
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To: PIF

“Any one care to put that medical science speak into simple English?”

Alzheimer’s is caused by a neurotoxin


39 posted on 10/18/2021 8:47:16 AM PDT by AppyPappy (How many fingers am I holding up, Winston? )
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To: BipolarBob

😆


40 posted on 10/18/2021 8:48:19 AM PDT by Bob434
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