Neurodegeneration—It’s Not the Tangles, It’s the T Cells

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Neurodegeneration—It’s Not the Tangles, It’s the T Cells

Post by TLS »

A new paper published March 8th is getting some good reviews as it considers T Cells

Here’s a tau twist that may take some adapting to. CD4+ and CD8+ T cells, yes, those mercurial executioners of the immune system, may be responsible for the neurodegeneration seen in Alzheimer’s disease and other tauopathies. That’s the scenario outlined by David Holtzman, Washington University, St. Louis, and colleagues in Nature on March 8. The scientists report that, in mice, microglia summon T cells into the brain and, perhaps by presenting antigens to them, kick them into overdrive. The cellular communication still needs to be deciphered. Even so, eliminating the T cells, or the microglia, forestalled neurodegeneration in tauopathy mice, though not in models of amyloidosis. Neuropathology data also suggest that T cells could provoke neurodegeneration in people who have AD.
  • In an ApoE4/tau transgenic mouse model, T cells enter the brain.
  • Some have clonally expanded in response to antigen.
  • Removing these T cells averts neurodegeneration, brain atrophy.
  • Does this mean Alzheimer’s is an autoimmune disease?
All told, the findings suggest that in the ApoE4 tauopathy model, T cells are being recruited to and activated in the brain, and could damage neurons. What causes this to happen is unknown, but existing hints point to microglia. For CD4+ and CD8+ T cells, activation typically begins when they interact with MHC class II and MHC class I antigen-presenting cells, respectively. This happens in lymph nodes. “Even in autoimmune diseases of the central nervous system, such as multiple sclerosis, antigen activation occurs outside the brain,” noted Holtzman.

https://www.alzforum.org/news/research- ... ts-t-cells
https://pubmed.ncbi.nlm.nih.gov/36890231/
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Re: Neurodegeneration—It’s Not the Tangles, It’s the T Cells

Post by NF52 »

Moderator's note: Thanks for finding and posting this important research using genetically engineered mice that have Apoe 4, with results that suggest immune T cells "get kicked into overdrive" as an upstream cause of tau tangles. I've added quotes to the Alz Forum article for clarity.
TLS wrote: Sat Mar 25, 2023 5:57 am A new paper published March 8th is getting some good reviews as it considers T Cells
Here’s a tau twist that may take some adapting to. CD4+ and CD8+ T cells, yes, those mercurial executioners of the immune system, may be responsible for the neurodegeneration seen in Alzheimer’s disease and other tauopathies. That’s the scenario outlined by David Holtzman, Washington University, St. Louis, and colleagues in Nature on March 8. The scientists report that, in mice, microglia summon T cells into the brain and, perhaps by presenting antigens to them, kick them into overdrive. The cellular communication still needs to be deciphered. Even so, eliminating the T cells, or the microglia, forestalled neurodegeneration in tauopathy mice, though not in models of amyloidosis. Neuropathology data also suggest that T cells could provoke neurodegeneration in people who have AD.
  • In an ApoE4/tau transgenic mouse model, T cells enter the brain.
  • Some have clonally expanded in response to antigen.
  • Removing these T cells averts neurodegeneration, brain atrophy.
  • Does this mean Alzheimer’s is an autoimmune disease?
All told, the findings suggest that in the ApoE4 tauopathy model, T cells are being recruited to and activated in the brain, and could damage neurons. What causes this to happen is unknown, but existing hints point to microglia. For CD4+ and CD8+ T cells, activation typically begins when they interact with MHC class II and MHC class I antigen-presenting cells, respectively. This happens in lymph nodes. “Even in autoimmune diseases of the central nervous system, such as multiple sclerosis, antigen activation occurs outside the brain,” noted Holtzman.
https://www.alzforum.org/news/research- ... ts-t-cells
https://pubmed.ncbi.nlm.nih.gov/36890231/
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Re: Neurodegeneration—It’s Not the Tangles, It’s the T Cells

Post by TLS »

Thank you! I will remember to add quotes next time.
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Re: Neurodegeneration—It’s Not the Tangles, It’s the T Cells

Post by JNB »

Hi,
I came across this article as well and it immediately got my attention. And I think it deserves more views.
Why APOE4 in Tsimane is cognitively protective!
70% of Tsimane have parasites, here is the study showing some evidence that the more parasitic worms APOE4 has the batter cognition outcome (in multiple tests). Worms activity was measured as a hallmark of eosinophilia count.
e4ts.jpg
How do worms affect the immune system
Extensive research shows that parasitic worms have the ability to deactivate certain immune system cells, leading to a gentler immune response.[2][3][4][5][6][7][8] Often, such a response is beneficial to both parasite and host, according to Graham Rook, a professor of medical microbiology at University College London.[9] This immune "relaxation" is incorporated throughout the immune system, decreasing immune responses against harmless allergens, gut flora, and the body itself.[9]
In the journal Parasite Immunology, Kamal et al. explains that parasitic worms often weaken the immune system's ability to effectively respond to a vaccine because such worms induce a Th2-based immune response that is less responsive than normal to antigens.[21] This is a major concern in developing countries where parasitic worms and the need for vaccinations exist in large number.[21] It may explain why vaccines are often ineffective in developing countries.[21]
Rook postulates that different parasitic worms suppress different Th types, but always in favor of regulatory T (Treg) cells.
https://en.wikipedia.org/wiki/Effects_o ... une_system

It always bugged me if AD goes with CVD why we see more prevalence of AD in women than in men...?

Sex differences in immune responses
Generally, adult females mount stronger innate and adaptive immune responses than males. This results in faster clearance of pathogens and greater vaccine efficacy in females than in males but also contributes to their increased susceptibility to inflammatory and autoimmune diseases.
For instance, 80% of autoimmune disease occurs in females
ims.jpg
https://www.nature.com/articles/nri.2016.90
Women tend to have more CD4+ T cells and less Treg cells (than men, regardless of APOE) trough most of their life.
APOE4 is just a hyperactive guard with hot guns.

Now another study
CD4+ effector T cells accelerate Alzheimer’s disease in mice
https://jneuroinflammation.biomedcentra ... 21-02308-7
Alteration in brain glucose uptake and its subsequent metabolism is a biomarker for memory impairment [24, 25], and has been used to confirm the effects of Aβ-Teffs on the memory functions of APP/PS1 mice.
These results underscore an important pathological role for CD4+ Teffs in AD progression. We posit that aberrant disease-associated effector T cell immune responses can be controlled. One solution is by Aβ reactive Tregs.
So the insulin resistance in brain is not a causation it's just a manifestation of the disease. Impaired neurons won't accept glucose well.
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Re: Neurodegeneration—It’s Not the Tangles, It’s the T Cells

Post by floramaria »

JNB wrote: Sat Feb 03, 2024 9:26 am Hi,
I came across this article as well and it immediately got my attention. And I think it deserves more views.
Why APOE4 in Tsimane is cognitively protective!
70% of Tsimane have parasites, here is the study showing some evidence that the more parasitic worms APOE4 has the batter cognition outcome (in multiple tests). Worms activity was measured as a hallmark of eosinophilia count.
e4ts.jpg
How do worms affect the immune system
Extensive research shows that parasitic worms have the ability to deactivate certain immune system cells, leading to a gentler immune response.[2][3][4][5][6][7][8] Often, such a response is beneficial to both parasite and host, according to Graham Rook, a professor of medical microbiology at University College London.[9] This immune "relaxation" is incorporated throughout the immune system, decreasing immune responses against harmless allergens, gut flora, and the body itself.[9]
In the journal Parasite Immunology, Kamal et al. explains that parasitic worms often weaken the immune system's ability to effectively respond to a vaccine because such worms induce a Th2-based immune response that is less responsive than normal to antigens.[21] This is a major concern in developing countries where parasitic worms and the need for vaccinations exist in large number.[21] It may explain why vaccines are often ineffective in developing countries.[21]
Rook postulates that different parasitic worms suppress different Th types, but always in favor of regulatory T (Treg) cells.
https://en.wikipedia.org/wiki/Effects_o ... une_system

It always bugged me if AD goes with CVD why we see more prevalence of AD in women than in men...?

Sex differences in immune responses
Generally, adult females mount stronger innate and adaptive immune responses than males. This results in faster clearance of pathogens and greater vaccine efficacy in females than in males but also contributes to their increased susceptibility to inflammatory and autoimmune diseases.
For instance, 80% of autoimmune disease occurs in females

ims.jpg
https://www.nature.com/articles/nri.2016.90
Women tend to have more CD4+ T cells and less Treg cells (than men, regardless of APOE) trough most of their life.
APOE4 is just a hyperactive guard with hot guns.

Now another study
CD4+ effector T cells accelerate Alzheimer’s disease in mice
https://jneuroinflammation.biomedcentra ... 21-02308-7
Alteration in brain glucose uptake and its subsequent metabolism is a biomarker for memory impairment [24, 25], and has been used to confirm the effects of Aβ-Teffs on the memory functions of APP/PS1 mice.
These results underscore an important pathological role for CD4+ Teffs in AD progression. We posit that aberrant disease-associated effector T cell immune responses can be controlled. One solution is by Aβ reactive Tregs.
So the insulin resistance in brain is not a causation it's just a manifestation of the disease. Impaired neurons won't accept glucose well.
Thanks for posting the links. The alteration in glucose uptake is the reason ketones can be so beneficial.
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Re: Neurodegeneration—It’s Not the Tangles, It’s the T Cells

Post by JNB »

floramaria wrote: Thu Feb 15, 2024 10:21 am
Thanks for posting the links. The alteration in glucose uptake is the reason ketones can be so beneficial.


Hi floramaria,
you're so kind and nice!

I think that ketones might help deliver direct energy to neurons (compared to glucose without insulin) but I don't think glucose/insulin energy issue is cause of the problem. I think it's a symptom of something else not working properly. I suspect that microglia is the key to neurodegeneration (mismanagement of immune system).
I think we should do our best to keep microglia flourish, calm and happy.
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Re: Neurodegeneration—It’s Not the Tangles, It’s the T Cells

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JNB wrote: Fri Feb 16, 2024 8:35 am
I think we should do our best to keep microglia flourish, calm and happy.
What are you doing to keep your microglia calm, happy and flourishing? Any tips?
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Re: Neurodegeneration—It’s Not the Tangles, It’s the T Cells

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floramaria wrote: Fri Feb 16, 2024 8:01 pm What are you doing to keep your microglia calm, happy and flourishing? Any tips?
That's a Million Dollar Question,

I don't know exactly, but I believe APOE4 has the strongest innate immune reaction and I suspect it is fueled by LDL.
So I think managing LDL levels is crucial.

I would avoid:

- foods high on saturated fat
- all processed vegetable oils and fats (except cold press olive oil and nuts in natural form (only eat the ones that you have to chew)),
- high GI foods
- ultra processed foods
- stress (increases LDL and glucose levels)
- sedentary life style
- toxins and chemicals exposure
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Re: Neurodegeneration—It’s Not the Tangles, It’s the T Cells

Post by floramaria »

JNB wrote: Mon Feb 26, 2024 2:08 pm That's a Million Dollar Question,

I don't know exactly, but I believe APOE4 has the strongest innate immune reaction and I suspect it is fueled by LDL.
So I think managing LDL levels is crucial.

I would avoid:

- foods high on saturated fat
- all processed vegetable oils and fats (except cold press olive oil and nuts in natural form (only eat the ones that you have to chew)),
- high GI foods
- ultra processed foods
- stress (increases LDL and glucose levels)
- sedentary life style
- toxins and chemicals exposure
Hi, JNB, does following your suggestions of what to avoid keep your LDL in a desirable range? Mine is always high. I do well on most of the things on your avoid list...except the first two! :oops:
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Re: Neurodegeneration—It’s Not the Tangles, It’s the T Cells

Post by JNB »

floramaria wrote: Sun Mar 03, 2024 9:38 pm Hi, JNB, does following your suggestions of what to avoid keep your LDL in a desirable range? Mine is always high. I do well on most of the things on your avoid list...except the first two! :oops:
Hi, mine always been slightly elevated through most of my life, high on stress + foods high on saturated fats (cheese, red meats, full fat dairy). I avoid high GI and sweet foods. I'm also very lean my BMI is about 20-21.
So I'm trying to stress less because it's not helpful, I also limited saturated fat intake and no vegetable oils (except cold pres extra virgin olive oil).
So we'll see I'd like to test my LDL levels by end of this month. I'd like to see my LDL in range of 100-120mg/dL.
From the picture below it's quite clear that LDL is in fact protective for noncardiovascular mortality, but that's not quite true for cardiovascular mortality. I'm not sure if I can get there, it's just very hard to avoid fat nowadays.
LDL.jpg
https://www.nature.com/articles/s41598- ... /figures/2
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