Researchers at the CUNY Graduate Center have made a groundbreaking discovery in Alzheimer’s disease research, identifying a critical link between cellular stress in the brain and disease progression.
Their study focuses on microglia, the brain’s immune cells, which play dual roles in either protecting or harming brain health. By targeting harmful microglia through specific pathways, this research opens new avenues for potentially reversing Alzheimer’s symptoms and providing hope for effective treatments.
Key Cellular Mechanism Driving Alzheimer’s Disease Identified
Researchers with the Advanced Science Research Center at the CUNY Graduate Center (CUNY ASRC) have unveiled a critical mechanism that links cellular stress in the brain to the progression of Alzheimer’s disease (AD). The study, published in the journal Neuron, highlights microglia, the brain’s primary immune cells, as central players in both the protective and harmful responses associated with the disease.
The Role of Microglia in Alzheimer’s
Microglia, often dubbed the brain’s first responders, are now recognized as a significant causal cell type in Alzheimer’s pathology. However, these cells play a double-edged role: some protect brain health, while others worsen neurodegeneration. Understanding the functional differences between these microglial populations has been a research focus for Pinar Ayata, the study’s principal investigator and a professor with the CUNY ASRC Neuroscience Initiative and the CUNY Graduate Center’s Biology and Biochemistry programs.
“We set out to answer what are the harmful microglia in Alzheimer’s disease and how can we therapeutically target them,” said Ayata. “We pinpointed a novel neurodegenerative microglia phenotype in Alzheimer’s disease characterized by a stress-related signaling pathway.”
Key Findings in Alzheimer’s Research
The research team discovered that activation of this stress pathway, known as the integrated stress response (ISR), prompts microglia to produce and release toxic lipids. These lipids damage neurons and oligodendrocyte progenitor cells—two cell types essential for brain function and most impacted in Alzheimer’s disease. Blocking this stress response or the lipid synthesis pathway reversed symptoms of Alzheimer’s disease in preclinical models.
Key Findings
- Dark Microglia and Alzheimer’s Disease: Using electron microscopy, the researchers identified an accumulation of “dark microglia,” a subset of microglia associated with cellular stress and neurodegeneration, in postmortem brain tissues from Alzheimer’s patients. These cells were present at twice the levels seen in healthy-aged individuals.
- Toxic Lipid Secretion: The ISR pathway in microglia was shown to drive the synthesis and release of harmful lipids that contribute to synapse loss, a hallmark of Alzheimer’s disease.
- Therapeutic Potential: In mouse models, inhibiting ISR activation or lipid synthesis prevented synapse loss and accumulation of neurodegenerative tau proteins, offering a promising pathway for therapeutic intervention.
“These findings reveal a critical link between cellular stress and the neurotoxic effects of microglia in Alzheimer’s disease,” said the study’s co-lead author Anna Flury, a member of Ayata’s lab and a Ph.D. student with the CUNY Graduate Center’s Biology Program. “Targeting this pathway may open up new avenues for treatment by either halting the toxic lipid production or preventing the activation of harmful microglial phenotypes.”
Implications for Alzheimer’s Treatment
This research underscores the potential of developing drugs that target specific microglial populations or their stress-induced mechanisms. “Such treatments could significantly slow or even reverse the progression of Alzheimer’s disease, offering hope to millions of patients and their families,” explained co-lead author Leen Aljayousi, a member of Ayata’s lab and a Ph.D. student with the CUNY Graduate Center’s Biology Program.
The study represents a major leap forward in understanding the cellular underpinnings of Alzheimer’s and emphasizes the importance of microglial health in maintaining overall brain function.
Reference: “A neurodegenerative cellular stress response linked to dark microglia and toxic lipid secretion” by Anna Flury, Leen Aljayousi, Hye-Jin Park, Mohammadparsa Khakpour, Jack Mechler, Siaresh Aziz, Jackson D. McGrath, Pragney Deme, Colby Sandberg, Fernando González Ibáñez, Olivia Braniff, Thi Ngo, Simira Smith, Matthew Velez, Denice Moran Ramirez, Dvir Avnon-Klein, John W. Murray, Jia Liu, Martin Parent, Susana Mingote, Norman J. Haughey, Sebastian Werneburg, Marie-Ève Tremblay and Pinar Ayata, 23 December 2024, Neuron.
DOI: 10.1016/j.neuron.2024.11.018
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13 Comments
Unpaywalled paper:
https://www.cell.com/cms/10.1016/j.neuron.2024.11.018/attachment/52008b63-1a2f-4dd9-8138-6a08f10f5e89/mmc5.pdf
“[“We set out to answer what are the harmful microglia in Alzheimer’s disease and how can we therapeutically target them,” said Ayata. “The study represents a major leap forward in understanding the cellular underpinnings of Alzheimer’s and emphasizes the importance of microglial health in maintaining overall brain function.” Therein lies most of the problem; more fatally-flawed treatment (drug) oriented research into now epidemic Alzheimer’s disease.
The researchers are targeting perpetual disruption of the cell stress factor instead of precluding/preventing it. With no funding source identified we can only infer that Big Pharma protocols prevailed. As a senior lay American male with a family and personal history of food allergies and dementia, and nutritional deficiency related short-term memory problems, respectively, I can state with substantial certainty that nearly subclinical non-IgE-mediated food allergies (Dr. Arthur F. Coca, by 1935) aggravated (or not) with FDA approved food poisoning (soy, TBHQ and MSG, minimally) is what causes the inflammation which upsets one’s delicate brain balance of essential glutamate and other amino acids. More details on my own still non-monetary video channel “About” page (https://odysee.com/@charlesgshaver:d?view=about).]”
When the microglia are toxified, the primary upregulated protein they excrete is Galetin-3 (GAL-3). This otherwise beneficial protein is then upregulated in abundance and becomes highly pro-inflammatory. This results in a negative feedback loop, resulting in all sorts of mayhem in the brain, including causing cells to excrete amyloid beta upstream. Downstream GAL-3 binds to the amyloid beta to form insoluble plaques and P-Tau tangles.
Identifying the root cause of the cellular insult causing the microglial to malfunction is multifactorial. Unless you’re willing to undergo a brain biopsy, it’s like finding a needle in a haystack.
Thanks to my parents’ doctor, I have become aware of a new investigational drug called TB006. To my knowledge, it is the first drug in history with the potential to reverse all dementias. It Targets GAL-3 and renders it bio-unavailable. At first, I was skeptical and did untold research, but mostly due to its incredible safety profile, I finally agreed to let my mom try it.
She was pretty far gone. Now she’s near normal after a few months of treatment! I accompanied my mom during treatments and spoke with other patients. They also had significant success with TB006.
If you don’t believe me, do as I did. I researched the target of TB006, Galectin-3, and became knowledgeable about what it can do to the brain and the rest of the body. Then, I looked further into what TB006 does to GAL-3. Once I understood, it was an easy decision I don’t regret. I have my mom back!
The manufacturer has doctors treating patients nationwide under an FDA approved Compassionate Use Program.
Thank you, Truebinding, for making this drug available to my mom! I wouldn’t have her today if not for you!
Merry Christmas and, on the ‘up’ side, congratulations, your efforts paid off and you have your mother back. In the 1990s there was only Cognex and we lost our mother to complications of dementia in early 1998. On the ‘down’ side, however, as only a lay victim-investigator-discoverer first learning of TrueBinding and TB006 this morning, I previously found that the three most ‘obvious’ common symptoms of what I describe above are: 1) obesity, 2) so-called “male-pattern-baldness” and 3) eyeglasses for myopia. Therefore, without a substantial change in dietary choices, first, I question what disorders not ‘side effects’ of TB006 might present next, if not already?
A brief visit to the TrueBinding website this morning revealed male-pattern-baldness among the top executives and a number of cases of obesity and eyeglasses among all of the ‘Team.’ Prematurely balding since the late 1960s with more than four decades of, at first, ignorant ingestion of FDA approved food poisoning, in late 2024 I’m only borderline obese and relatively healthy but I’m again/still free of any prescription treatments and living independently in four season central Wisconsin, at age eighty-one. Again, congratulations on having your mother back but keep a keen eye open for other non-side effect disorders which may yet appear (if not already), due to TB006 not treating the root causes, unless it does.
Obvious shill post from Truebinding Employee #26
Hi, What can you tell me or direct me towards any recent findings, clinical trials or break throughs on Parkinsons Disease? I’ve heard that 1979 was likely the last year any real progress was made concerning Sinemet and PD
This is the greatest Christmas gift ever both my parents died from this terrible disease if it called that anymore it’s time the truth is out to let people understand it a number one killer thanks to all the family and family members whom let there love ones be used in a trail period over twenty years of studie I believe we can change the outcome. God bless everyone for the time and effort to make this happen.
As someone who has reversed their early onset, Im glad someone acknowledged the cellular stress.
That’s the actual culprit.
The 2nd culprit is the entire industry that has chosen to ignore some of our most basic biological data that has been available for over half a century now, that’s where I found answers.
Where can I find this data? What articles have you read and what changes/additions have you made to your lifestyle in order to holt this process?
Microglia are monocyte-like cells which are embryologically derived from the yolk-sac, not the bone marrow, as are the Kuppfer cells in the liver. We know that large swings in blood sugar cause activation of the NLRP3 inflammatory pathway in the monocytes/macrophages in the gut. This releases interleukins and caspase which activate Kuppfer cells to create liver inflammation and fibrosis. It is logical to extend that signalling system to the brain which indicates that a diet high in sugar, particularly high fructose corn syrup will tend to increase the likelihood of dementia of the Alzheimer’s type.
Some interesting new to me perspectives, David, but a quick search confirms for me that Alzheimer’s disease presented by 1906 and HFCS wasn’t invented until 1957. Furthermore, food allergies go back millennia and my kind of nearly subclinical non-IgE-mediated food allergies were first identified, studied and reported on by 1935. In my immediate family dementia didn’t present until well after added artificially cultured “free” (can cross the blood-brain barrier) MSG was FDA approved for expanded use in 1980.
For me personally beginning in 1981 due to my own lay food allergy ignorance, findings and practices, I didn’t experience short-term memory problems until (along with unreliable serum testing) I inadvertently made myself seriously deficient of calcium and very seriously deficient of phosphorus in 2009 and 2021, respectively. Now eighty-one years of age and still ingesting plenty of various sugars, I find it is the very, very mild inflammation of my very mild food allergy reactions aggravated with added MSG that does the damage and the calorie, carbohydrate, fats, oils, laziness, sugar things are just dogmatic medical myths. More on the “About” page of my video channel linked to in my first comments above.
This study confirms the findings presented in Dr. Jackson Nakazawa’s book, The Angel & The Assassin, that came out in 2020, explaining the research that was done at MIT, and the effect of 40 Hz waves (sound or light) to re-set the microglia, and that the brain is more connected with the rest of the body than people thought; stress triggers the autoimmune response, manifested across the body & brain. Go get that book! Merry Christmas & Happy New Year!
Thank you, Rosemary, for opening a door to potential improvements I didn’t know existed: Donna (not Dr.) Jackson Nakazawa. I just visited her website and I’m now trying to communicate with her to learn if she knows anything about the allergy/MSG/calcium deficiency, minimally, factors. Hope you’ve had a merry Christmas and will have a great new year.