The blood-brain barrier weakens during normal aging and in neurodegenerative disease, but the reasons are not fully understood. In the February 26 Nature, scientists led by Tony Wyss-Coray and Carolyn Bertozzi at Stanford University, California, venture a suggestion. In mice, they found that mucin-domain glycoproteins, components of the carbohydrate meshwork that lines the interior of brain blood vessels, wane with age. In young mice, thinning out these sugary, bottlebrush-shaped proteins made brain blood vessels leak. Conversely, promoting glycosylation of the proteins in old mice firmed up the blood-brain barrier. This even helped prevent memory slippage.
The findings may be relevant to neurodegeneration. The authors detected a scarcity of mucin-domain glycoproteins in blood vessels from postmortem Alzheimer’s and Huntington’s brains. This could contribute to leaky blood vessels in those disorders, they suggested. Wyss-Coray considers glycosylation to be understudied in general. “We believe there is a vast trove of molecular information to be discovered by unlocking the patterns of glycosylation on molecules and cells,” he wrote to Alzforum.
In future work, the authors will further explore how glycosylation in the glycocalyx changes with age and disease in different brain regions. They also want to identify the underlying proteins that serve as scaffolds for mucin-type O-glycosylation in the glycocalyx.
Commenters agreed the findings point toward new therapeutic strategies. “The ability to target the glycocalyx with viral vectors suggests that this work could be translated, either through viral vectors or drugs that target the enzymes that form the glycocalyx, to restore BBB function during aging or neurological disease,” Kipnis and Smyth wrote.
https://www.alzforum.org/news/research-news/do-specialized-glycoproteins-prop-blood-brain-barrier
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This key protein could be responsible for brain ageing
An amyloid protein targeted by Alzheimer’s disease therapies seems to be involved in normal mental decline.
A protein involved in Alzheimer’s disease progression has been linked to normal brain ageing, raising the prospect that researchers could target it to stave off age-related mental decline.
The amyloid-β precursor protein (APP) helps to form links between the brain’s neurons. It has been highly studied because its breakdown creates amyloid-β peptides, which are often present in plaques in the brains of people with Alzheimer’s disease.
Now, Dario Valenzano, an evolutionary biologist at the Leibniz Institute on Aging in Jena, Germany, and his colleagues have found that knocking out the appa gene, which makes APP, in turquoise killifish (Nothobranchius furzeri) reduces signs of ageing.
“We found that there is probably an overlooked role of amyloid precursor protein in normal brain ageing,” says Valenzano. The work has not yet been peer reviewed and is posted on the bioRxiv preprint server1.
Full article: This key protein could be responsible for brain ageing
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Long-Term Exposure to Non-Steroidal Anti-Inflammatory Medication in Relation to Dementia Risk
https://agsjournals.onlinelibrary.wiley.com/doi/10.1111/jgs.19411
“Long-term NSAID use, but not cumulative dose, was associated with decreased dementia risk. This suggests that prolonged rather than intensive exposure to anti-inflammatory medication may hold potential for dementia prevention.”
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Why women are more likely to get Alzheimer’s
At a time when including the word “women” in research grants has triggered special review at the NIH, the journal Science has published an entire special issue devoted to new research and perspectives on women’s health. The collection, out yesterday, highlights studies on the interplay between hormones, chromosomes, and dementia, and includes essays arguing for the importance of studying sex differences throughout biomedical research.
“The menopause transition specifically might be an important key to help us unlock the biology of Alzheimer’s disease, and this is knowledge that will promote health for all brains,” Madeline Wood Alexander, one of the study authors, said to STAT’s Liz Cooney. Read more from Liz on the findings and what research is still needed.
full article: ‘Simply good science’: Women’s health research reveals clues to aging and Alzheimer’s - Under fire in the U.S., researchers on sex differences highlight need to understand ‘all brains’
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Elucidating the downstream impact of exogenous hormones on the aging brain will have far-reaching consequences for understanding why Alzheimer’s disease (AD) predominates in women almost twofold over men. We tested the extent to which menopausal hormone therapy (HT) use is associated with later-life amyloid-β (Aβ) and tau accumulation using PET on N = 146 baseline clinically normal women, aged 51 to 89 years. Women were scanned over a 4.5-year (SD, 2.1; range, 1.3 to 10.4) and 3.5-year (SD, 1.5; range, 1.2 to 8.1) period for Aβ and tau, respectively, ~14 years after the initiation of HT. In older women (aged >70 years), HT users exhibited faster regional tau accumulation relative to non-users, localized to the entorhinal cortex and the inferior temporal and fusiform gyri, with an indirect effect of HT on cognitive decline through regional tau accumulation. In younger women (aged <70 years), HT associations with tau accumulation were negligible. Findings are relevant for optimizing menopausal treatment guidelines.
Open Access Paper:
https://www.science.org/doi/10.1126/sciadv.adt1288
Oy vey, these people are so bitterly entrenched in a narrative, they can’t help themselves.
Sleep habits are so difficult to fix. For me, they’ve been the most difficult aspect of a healthy lifestyle. Not all of us are Bryan Johnson.
Stiv
#500
Might explain why naproxen was on a list of ‘longevity’ compounds discussed by Matt Kaeberlein
This sounds pretty terrifying (and I do have skin in this having taken estradiol/progesterone for about 26 years starting at age 42).
But no, is a confirmation of the “timing hypothesis” which has been known for some time: if you start early, at the time of menopause or not later than about 5 years after menopause, HRT (estradiol + natural progesterone, not premarin/ synthesized progesterone) it is generally a good thing. But if you start later, in your sixties, it can be a problem.
When I first saw this headline I could immediately feel my heart beating wildly. As readers of my posts may recall I am particularly freaked out by the prospect of AD.
But no, nothing to see here.
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Dale Bredesen has a very clear (with diagrams) explanation about APP splicing in his book The End of Alzheimers. He targets it as the fundamental cause and as I read more about AD I am more ad more inclined to see it this way – and that is also consistent with this bioRxiv publication.
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splicing, of course, lies behind pretty well all of the aging phenotype (although there are also issues with senescence which is more linked to a failure of differentiation).
There are two theories as to why splicing is an aging problem
a) That of Professor Lorna Harries of Exeter University, UK who argues it is linked to the availabilty of splicing factors.
b) My hypothesis that splicing decisions are driven by acetylation (not only of the histone, but of other things as well although the histone is important) and is part of the system whereby the efficiency of the mitochondria controls what proteins are produced.
Actually these two theories may be linked as the acetylation may drive splicing factors. My hypothesis is IMO better because it explains why it happens.
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Asking ChatGBP 4o
what are the links between cytosolic acetyl-CoA levels and mRNA splicing
ChatGPT said:
Cytosolic acetyl-CoA levels are linked to mRNA splicing through multiple mechanisms, primarily via histone acetylation and the regulation of splicing factors. Here’s how:
1. Histone Acetylation and Chromatin Structure
- Acetyl-CoA is a key donor for histone acetylation, a process that relaxes chromatin structure and promotes transcriptional activation.
- Changes in chromatin structure can influence co-transcriptional splicing, where splicing factors are recruited to nascent transcripts based on chromatin modifications.
2. Acetylation of Splicing Factors
- Acetyl-CoA is required for the acetylation of splicing factors, which can alter their activity, localization, or interactions with pre-mRNA.
- Example: hnRNPs and SR proteins, key regulators of alternative splicing, can be acetylated, affecting their function.
3. Energy and Metabolic Signaling
- High cytosolic acetyl-CoA levels are associated with active metabolic states, which can impact mRNA splicing patterns in response to cellular conditions.
- Metabolic sensors (e.g., SIRT1, AMPK) regulate splicing factor activity in response to acetyl-CoA availability.
4. Direct Impact on RNA Polymerase II (RNAPII)
- Acetylation marks on histones influence RNAPII elongation rates, which in turn affect exon inclusion or skipping in alternative splicing.
Conclusion
Changes in cytosolic acetyl-CoA levels can modulate histone acetylation, splicing factor function, and transcription elongation, ultimately influencing mRNA splicing outcomes. This highlights a key link between cellular metabolism and gene expression regulation.
Stiv,
Could you say more about naproxen?
I am not familiar with Matt K.
Hi Deborah, can you provide more info or sources on the timing hypothesis?
Also, how do you get that the charts above relate to timing? My reading is baseline age is the age at the start of the study, not the age at initiation of HT.
