Rapamycin Increases Alzheimer’s-Associated Plaques in Mice

[Mito]

Summary: Rapamycin, a drug approved for the treatment of cancer and transplant patients increases amyloid-beta protein plaques in the brains of mice.

Source: UT San Antonio

Researchers from The University of Texas Health Science Center at San Antonio (UT Health San Antonio) have found that oral administration of rapamycin to an Alzheimer’s disease mouse model causes an increase in beta (β)-amyloid protein plaques. β-amyloid buildup is a hallmark of Alzheimer’s disease.

Rapamycin is approved to treat transplant and cancer patients. Publicly available data suggest that the drug might also improve learning and memory in aged mice. However, the UT Health San Antonio researchers observed that after rapamycin treatment, a protein called Trem2 (triggering receptor expressed on myeloid cells 2) is dramatically diminished. Trem2 is present in microglia, which are immune cells in the brain and spinal cord.

“Trem2 is a receptor located on the surface of the microglia, and it enables these cells to engulf and degrade β-amyloid,” said study senior author Manzoor Bhat, PhD.

“Loss of Trem2 in microglia impairs the vital function of amyloid degradation, which in turn causes a buildup of β-amyloid plaques.” Dr. Bhat is professor and chairman of the Department of Cellular and Integrative Physiology at UT Health San Antonio and vice dean for research in the university’s Joe R. and Teresa Lozano Long School of Medicine.

Drug target

Importantly, the study, published June 7 in the Journal of Neuroscience, also featured a novel way to increase Trem2 in microglia. When the study lead author, Qian Shi, PhD, assistant professor in the Department of Cellular and Integrative Physiology, deleted a gene called Tsc1 from the microglia, there was a marked increase in Trem2 levels and a decrease in β-amyloid plaques.

Previous research has shown that loss of Tsc1 leads to activation of the mTOR (mammalian target of rapamycin) signaling pathway. Rapamycin, in contrast, blocks this pathway.

“We expected that selective loss of Tsc1, only in microglia and not in neurons or other cells, would have negative consequences because inhibiting mTOR with rapamycin has known therapeutic uses in some disease models,” Dr. Shi said.

“But the opposite was occurring.” Thus, repressing Tsc1 solely in microglia to enhance β-amyloid uptake could be a potential drug target, Dr. Shi said.

Rapamycin Increases Alzheimer’s-Associated Plaques in Mice - Neuroscience News

Rapamycin, a drug approved for the treatment of cancer and transplant patients increases amyloid-beta protein plaques in the brains of mice.

neurosciencenews.com

 

[aliml]

Defect in TREM2 impairs mTOR activation and elicits AMPK activation, autophagy and cell death in microglia.

TREM2 maintains microglial metabolic fitness in Alzheimer’s disease

Elevated risk of developing Alzheimer’s disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering and phagocytosis. How ...

ncbi.nlm.nih.gov

Rapamycin is an mTOR inhibitor, and AMPK activation results in the reduction of mTOR.

mTOR Activators​

The main activators of mTOR are a variety of amino acids and the hormone insulin. Testosterone is also capable of activating mTOR [57, 58].

• Proteins, especially if rich in leucine
• Excess calories
• Excess carbs
• Exercise [25, 26]
• Orexin [59]
  • Glycine
  • Caffeine
  • CO2
  • Fructose
• IGF-1 [3]
• Insulin
• Testosterone [58]
• Ghrelin [6]
• Leptin [60]
• Thyroid hormone [61]
• Oxygen
• Ketamine [62]

All About mTOR + Natural mTOR Inhibitors & Activators - SelfHacked

High mTOR levels may shorten your lifespan. Read on to learn what it is, what it does, and how to block it naturally with diet & lifestyle.

selfhacked.com

AMPK Inhibitors​

• Leptin [4]
• Insulin [2]
• GLP-1 [2]
  • Resistant starch
  • Butyrate
  • Olive oil
  • Cinnamon
  • Fructose
  • Berry and Citrus
  • Chlorogenic acid
  • Olive leaf extract
  • Grape Seed Extract
  • Berberine
  • Resveratrol
  • Bile supplements
  • Ginseng
  • Alpha-linolenic acid
  • Whey
  • Glutamine
  • Bitter melon
  • Quercetin
• Estradiol [2]
• Lipoic acid [19, 13]
• Quercetin [20]
• Nicotine [60]
• Ketones [61]

AMPK: Metabolism & Insulin + Ways to Activate - SelfHacked

AMPK stimulates metabolism, improves insulin sensitivity, and promotes fat burning. Can it be activated through lifestyle and supplements?

selfhacked.com

 

[S.Seneff]

Cancer patients had lower risks of dementia (hazard ratio: 0.89, confidence interval: 0.81-0.98) and its subtypes (Alzheimer's disease [AD]: 0.85 [0.74-0.98]

Investigating the association between cancer and dementia risk: a longitudinal cohort study

Previous studies found that cancer survivors had a reduced risk of dementia compared with the general population. However, these findings were uncertain because of survivor bias and a lack of stratification by cancer types. This current cohort study used ...

www.ncbi.nlm.nih.gov

 

[Michael Mohn]

Good posts!

 

[No_Energy]

Various other articles seem to suggest the opposite. now where does truth lie?..

Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-β Levels in a Mouse Model of Alzheimer's Disease​

Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-β Levels in a Mouse Model of Alzheimer's Disease

Background Reduced TOR signaling has been shown to significantly increase lifespan in a variety of organisms [1], [2], [3], [4]. It was recently demonstrated that long-term treatment with rapamycin, an inhibitor of the mTOR pathway[5], or ablation of the mTOR target p70S6K[6] extends lifespan in...

journals.plos.org

 

[Momma]

@frannybananny @Tarmander @Blossom

 

[Blossom]

Thank you @Momma. I don’t really know the answer but in light of the multiple other benefits I’m opting to continue our experiment on myself, my husband and my dog. I have seen science on both sides but I don’t believe anyone knows for certain yet if the intermittent doses used for longevity increases risk. It would be interesting to know if people taking it for anti rejection purposes have increased AD/dementia. I did read this which is interesting.
“The only study to begin rapamycin treatment both early and late in pathogenesis (in a mouse model that expressed mutant APPK670N,M671L, PSEN1M146V, and MAPTP301L) revealed that rapamycin can only prevent, but not reverse, the accumulation of amyloid plaques and MAPT tangles, as well as learning and memory deficits [15]. A human who has just been diagnosed with dementia caused by AD will carry significant amyloid plaque and MAPT tangle pathology that has been developing for decades. Starting rapamycin treat- ment in someone with dementia will likely mimic the late intervention in Majumder et al. [15], which did not work. This is consistent with our hypothesis that augmenting lyso- somal-system clearance late in AD is futile, or possibly dele- terious (by clogging the failing lysosomal system). This brings us to our second point that treating people with dementia is not the same as treating at-risk individuals before the onset of pathology or early in the disease process. The consensus of
AUTOPHAGY 1461

1462 J. M. CAROSI AND T. J. SARGEANT
available preclinical data is that rapamycin could be useful to prevent the onset or early development of AD neuropathology rather than as a treatment for dementia.
Given the considerations outlined above, we propose that rapamycin should not be used in people with clinical signs of dementia. Rather, we propose that research efforts should focus on exploring prevention of amyloid plaque and MAPT tangle accumulation early in the disease process. This would involve recruiting people who are positive for amyloid plaque burden but who are still in mid-life. A trial using rapamycin in such a cohort would likely succeed in delaying signs of dementia. Trials using rapamycin in cohorts that are already affected by dementia will have a much higher chance of failure, as this drug will further damage an irreparably injured lysosomal system.”

 

[Blossom]

Then there’s this one in mice.
“The present studies, together with our previous work, identify mTOR as a critical driver of NVC impairment in a model of AD through the inhibition of nNOS and non-NOS-dependent components of NVC (Fig. 7). Our studies show that mTOR attenuation can both prevent and reverse NVC deficits and attendant AD-like memory deficits, suggesting that mTOR inhibitors, available in the clinic, have tangible potential for the prevention and/or treatment of AD. Since cerebrovascular dysfunction emerges at the earliest stages of AD, restoration of brain vascular function with rapamycin may delay onset and/or slow disease progression in AD and potentially other age-associated dementias.”

mTOR Attenuation with Rapamycin Reverses Neurovascular Uncoupling and Memory Deficits in Mice Modeling Alzheimer's Disease

Vascular dysfunction is a universal feature of aging and decreased cerebral blood flow has been identified as an early event in the pathogenesis of Alzheimer's disease (AD). Cerebrovascular dysfunction in AD includes deficits in neurovascular coupling ...

www.ncbi.nlm.nih.gov

Edit: this link might be based on the same research posted earlier in the thread by @No_Energy

 

[sunny]

.

 

[Tarmander]

Here is the actual study: Microglial mTOR Activation Upregulates Trem2 and Enhances β-Amyloid Plaque Clearance in the 5XFAD Alzheimer's Disease Model

Doesn't worry me at all.

5XFAD AD is a late stage AD mouse model

"In the hAPP-J20 AD mouse model, rapamycin has been shown to reduce Aβ plaque deposition and Tau protein aggregation when it was applied to the mice before the disease onset"

So study says if you have late stage AD, poisoning yourself by inhibiting mTor completely is bad.