7 ms·

Doesn't this boost the hypothesis that Alzheimer's is closely related to insulin resistance in the brain? What some people call type III diabetes. I ask becaus

Doesn't this boost the hypothesis that Alzheimer's is closely related to insulin resistance in the brain? What some people call type III diabetes. I ask because one of the hallmarks of insulin resistance is the presence of lipid droplets in close proximity to mitochondria [0]. [0] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10455923/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10455923/

echelon 3y ago
Here's what the authors speculate [1], > A recent report showed that innate immune triggers (for example, Escherichia coli and Salmonella) induce LD formation in peripheral macrophages as part of an evolutionarily conserved antimicrobial defence in which LDs coated with antimicrobial proteins, such as cathelicidin (CAMP), kill bacteria8. We speculate that a similar programme can be triggered in human microglia exposed to Aβ, LPS and other innate immune activators and disrupt brain homeostasis. Protein aggregates found in other neurodegenerative diseases may trigger the LDAM state. For example, alpha-synuclein binding to TLR2 and TLR5 induces microglial NLRP3 inflammasome activation, which is a shared signature seen in LDAM36. Given that we recently identified that LDAM are abundant in the ageing mouse brain, LDAMs may also be triggered by hitherto unknown protein aggregates and innate immune activators which accumulate with age. Interestingly, the most enriched pathway in human LD-containing iMGs is ‘cellular senescence’, similar to lipid-laden ‘foamy macrophages’ in atherosclerosis which have a senescent phenotype and are drivers of pathology37. Perhaps in the natural ageing of various organs, LD-accumulating tissue-resident macrophages represent a general class of senescent myeloid cells which are drivers of tissue inflammation. It could be a lot of things, and there might be multiple pathways that lead to this state. [1] https://www.nature.com/articles/s41586-024-07185-7#Sec6 https://www.nature.com/articles/s41586-024-07185-7#Sec6
m463 3y ago
sleep problems (like sleep apnea) affect insulin resistance and weight gain. This goes with other evidence that not sleeping correlates with alzheimers. So the fat buildup correlates in a different way.
levocardia 3y ago
There's a really interesting paradox where, compared to healthy adults, intramuscular lipid droplet storage near mitochondria is increased in: 1) People with obesity 2) People with type 2 diabetes 3) People who do endurance exercise Even though #3 is highly protective against #1 and #2. The best explanation I've seen is that the important difference is why the lipid droplets are being deposited [1] [1] https://link.springer.com/article/10.1007/s00424-005-1509-0 https://link.springer.com/article/10.1007/s00424-005-1509-0
- teaearlgraycold 3y ago
  If I am rich enough to have a down payment for a Bay Area house I’ll be tremendously in debt. But that wouldn’t put me in the same boat as someone with oodles of credit card debt. I’m guessing in endurance athletes it’s there because it’s about to be used. In the obese it’s there because they’re running out of places to put fat.
  - levocardia 3y ago
    Right - but even then, if a super fit endurance athlete stops exercising, they don't immediately become diabetic. The upstream cause (what biochemical stimulus is driving the fat deposition?) is probably where the key insight lies.
    - teaearlgraycold 3y ago
      Well yeah. You’re measuring the output to a multi-variate function. There should be no expectation that this one output drives other occasionally correlated outputs to other functions.
    - aulin 3y ago
      If I recall correctly there were some studies that actually showed endurance runners have higher type 2 diabetes risk. And the suspect cause was the diet, specifically the carb loading practice and the abuse of high sugar products during the activity. So the three categories may actually share the same baseline, insulin resistance. It was quite controversial when it emerged (see Tim Noakes story), not sure if it's more accepted these days.
criddell 3y ago
If it does boost that hypothesis, what then? Are there things you can do aside from the basic focus on diet, exercise, and sleep?
- aoeusnth1 3y ago
  I assume: avoid sugar.
  - criddell 3y ago
    I think that would be covered by focus on diet and sleep.
- lhuser123 3y ago
  https://brainenergy.com/ https://brainenergy.com/ Highly recommend. I think is what you are looking for.
- onionisafruit 3y ago
  If this proves out we focus on finding the precise mechanism and how to disrupt it.
- rednerrus 3y ago
  Peptides.
lhuser123 3y ago
Plausible. I think this was also addressed in the work of Christopher Palmer. https://brainenergy.com/ https://brainenergy.com/ “Mental disorders are metabolic disorders of the brain”
- EdwardDiego 3y ago
  All of them?
  - rednerrus 3y ago
    Why would this be shocking?
    - error_logic 3y ago
      I wouldn't call it metabolic if parts were missing or otherwise had communication malfunctions without any issue in acquiring/using energy itself. But I'm sure lots of things go wrong when the brain doesn't get the energy it needs and is forced to compensate. Even more to the point: If something generalizes without a qualifier like most/many/some/can be, there might be an implicit "all/every" (or careless communication) and that makes it all suspect.
ransom1538 3y ago
I am swallowing berberine now. Many studies show that berberine can significantly lower blood sugar levels in people with type 2 diabetes ( 8 ). It seems to work via multiple mechanisms and may help ( 9 , 10 ): decrease insulin resistance, making the blood sugar-lowering hormone insulin more effective.

echelon 3y ago

Here's what the authors speculate [1], > A recent report showed that innate immune triggers (for example, Escherichia coli and Salmonella) induce LD formation in peripheral macrophages as part of an evolutionarily conserved antimicrobial defence in which LDs coated with antimicrobial proteins, such as cathelicidin (CAMP), kill bacteria8. We speculate that a similar programme can be triggered in human microglia exposed to Aβ, LPS and other innate immune activators and disrupt brain homeostasis. Protein aggregates found in other neurodegenerative diseases may trigger the LDAM state. For example, alpha-synuclein binding to TLR2 and TLR5 induces microglial NLRP3 inflammasome activation, which is a shared signature seen in LDAM36. Given that we recently identified that LDAM are abundant in the ageing mouse brain, LDAMs may also be triggered by hitherto unknown protein aggregates and innate immune activators which accumulate with age. Interestingly, the most enriched pathway in human LD-containing iMGs is ‘cellular senescence’, similar to lipid-laden ‘foamy macrophages’ in atherosclerosis which have a senescent phenotype and are drivers of pathology37. Perhaps in the natural ageing of various organs, LD-accumulating tissue-resident macrophages represent a general class of senescent myeloid cells which are drivers of tissue inflammation. It could be a lot of things, and there might be multiple pathways that lead to this state. [1] https://www.nature.com/articles/s41586-024-07185-7#Sec6 https://www.nature.com/articles/s41586-024-07185-7#Sec6

m463 3y ago

sleep problems (like sleep apnea) affect insulin resistance and weight gain. This goes with other evidence that not sleeping correlates with alzheimers. So the fat buildup correlates in a different way.

levocardia 3y ago

There's a really interesting paradox where, compared to healthy adults, intramuscular lipid droplet storage near mitochondria is increased in: 1) People with obesity 2) People with type 2 diabetes 3) People who do endurance exercise Even though #3 is highly protective against #1 and #2. The best explanation I've seen is that the important difference is why the lipid droplets are being deposited [1] [1] https://link.springer.com/article/10.1007/s00424-005-1509-0 https://link.springer.com/article/10.1007/s00424-005-1509-0

teaearlgraycold 3y ago
If I am rich enough to have a down payment for a Bay Area house I’ll be tremendously in debt. But that wouldn’t put me in the same boat as someone with oodles of credit card debt. I’m guessing in endurance athletes it’s there because it’s about to be used. In the obese it’s there because they’re running out of places to put fat.
- levocardia 3y ago
  Right - but even then, if a super fit endurance athlete stops exercising, they don't immediately become diabetic. The upstream cause (what biochemical stimulus is driving the fat deposition?) is probably where the key insight lies.
  - teaearlgraycold 3y ago
    Well yeah. You’re measuring the output to a multi-variate function. There should be no expectation that this one output drives other occasionally correlated outputs to other functions.
  - aulin 3y ago
    If I recall correctly there were some studies that actually showed endurance runners have higher type 2 diabetes risk. And the suspect cause was the diet, specifically the carb loading practice and the abuse of high sugar products during the activity. So the three categories may actually share the same baseline, insulin resistance. It was quite controversial when it emerged (see Tim Noakes story), not sure if it's more accepted these days.

criddell 3y ago

If it does boost that hypothesis, what then? Are there things you can do aside from the basic focus on diet, exercise, and sleep?

aoeusnth1 3y ago
I assume: avoid sugar.
- criddell 3y ago
  I think that would be covered by focus on diet and sleep.
lhuser123 3y ago
https://brainenergy.com/ https://brainenergy.com/ Highly recommend. I think is what you are looking for.
onionisafruit 3y ago
If this proves out we focus on finding the precise mechanism and how to disrupt it.
rednerrus 3y ago
Peptides.

lhuser123 3y ago

Plausible. I think this was also addressed in the work of Christopher Palmer. https://brainenergy.com/ https://brainenergy.com/ “Mental disorders are metabolic disorders of the brain”

EdwardDiego 3y ago
All of them?
- rednerrus 3y ago
  Why would this be shocking?
  - error_logic 3y ago
    I wouldn't call it metabolic if parts were missing or otherwise had communication malfunctions without any issue in acquiring/using energy itself. But I'm sure lots of things go wrong when the brain doesn't get the energy it needs and is forced to compensate. Even more to the point: If something generalizes without a qualifier like most/many/some/can be, there might be an implicit "all/every" (or careless communication) and that makes it all suspect.

ransom1538 3y ago

I am swallowing berberine now. Many studies show that berberine can significantly lower blood sugar levels in people with type 2 diabetes ( 8 ). It seems to work via multiple mechanisms and may help ( 9 , 10 ): decrease insulin resistance, making the blood sugar-lowering hormone insulin more effective.