Bonehead! Hormone from Bone Causes Cognitive Decline

Astonishing new research that absolutely blew my mind was just published in Nature Metabolism, linking bone to brain. Specifically, these researchers found that a hormone secreted from the bone can promote Alzheimer's disease, opening up new inroads for strengthening bone and brain. In this video, I'll go through the paper step by step, highlighting what the researchers did, and if you stick around, I'll reveal something personal and rather shocking about why I love these data so much.

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Stay curious. The paper itself, published in Nature Metabolism, is entitled "Osteocyte"— that's a bone cell— "Derived Sclerostin"— that's the hormone— "Impairs Cognitive Function During Aging and Alzheimer's Disease Progression." So first, for a little bit of background, bone can actually function as an endocrine organ. That means it secretes hormones called osteokines. One of these osteokines is called sclerostin, which circulates around in the blood and then can bind to receptors on cells called LRP5 and 6 receptors to inhibit a pathway called Wnt-beta-catenin signaling pathway. In doing so, sclerostin can impair bone formation in bones and also in the brain it can impact neuron function. Actually, I've done quite a bit of research on this pathway myself and its role in Alzheimer's disease, so I have a fair bit of background on this topic already. Interestingly, sclerostin actually increases with age. You can think of it as a marker of aging of sorts. And sclerostin levels are also increased in various metabolic diseases that are in themselves associated with Alzheimer's, like diabetes. Leading the authors to hypothesize that maybe, just maybe, sclerostin from bone could cross through the blood-brain barrier into the brain and impact brain function. Although this was a, I think, pretty bold hypothesis and never actually been tested. First, what they do in this paper is that they show that sclerostin levels in the brain's cerebral spinal fluid, the fluid bathing the brain, actually increase with age in men and in women, which you can see here. On the x-axis you have age in years, and on the y-axis you have cerebral spinal fluid sclerostin. You can see a very clear trend towards older, higher levels of CSF sclerostin. So sclerostin can kind of be a marker of aging, it increases with aging. And the next obvious question is, well, can sclerostin, presumably made from the bone in the periphery, actually cross through the blood-brain barrier? Spoiler alert, yes. They're able to show that sclerosin can cross through the blood-brain barrier by injecting tagged sclerosin into the tail veins of mice, and then after sacrificing the mice, staining their brains for tagged sclerosin. And you can see here images from the mice's brains indicating the arrowheads in the sclerosin-injected mice show clear accumulation of sclerosin in the brains as compared to the control mice. So they know that sclerosin levels are associated with aging in humans, and sclerostin can cross through the blood-brain barrier, at least in mice. But can sclerostin actually cause cognitive dysfunction? To test this, they genetically engineered mice to express more sclerostin. These are the transgenic, or TG as abbreviated in the paper, mice. And they shockingly found that sclerostin transgenic mice had worse cognitive function and decreased synaptic plasticity, which is the process that underlies learning and memory. And that's shown here in these figures. In the figure that's testing cognitive function, it's something called a water maze test, a Morris water maze test. And basically the idea is the longer the mouse takes to escape, the worse their memory. And so there's more movement around, more searching for the platform to escape in the transgenic mice. And then what you see with respect to this figure are the field excitatory postsynaptic potentials, which are a measure of long-term potentiation, basically the process underlying memory. Big picture here, basically they're showing sclerostin in these mice, overexpressing sclerostin, have impaired cognitive function and impaired synaptic plasticity, process underlying learning. And they also did the converse just to really hammer the point home and knocked out sclerostin from some mice, which you'd expect to improve cognitive function. And indeed, they found in these sclerostin knockout KO mice, cognitive function was improved. So bottom line, these exciting data indicate that increased serum concentrations of sclerostin can impair cognitive function and synaptic plasticity, at least in mice. They then went to dive into the mechanism to see how, how does sclerostin possibly do this, that sclerostin increased amyloid beta production, a hallmark of Alzheimer's disease. Disease. Basically what they did is they took neuroblast cells and treated them with sclerostin and measured levels of a protein that processes the amyloid precursor protein into amyloid beta, the pathological harm— hallmark of Alzheimer's disease. And indeed they found an increase in the beta secretase protein that processes amyloid beta and increases in amyloid beta, which you can see clearly here and in the blue bar where the sclerostin SCL mice had much higher levels of amyloid beta. Thus, sclerostin not only worsens cognitive function and worsens synaptic plasticity, but there's also a clear mechanism by which it does so. So to investigate then whether sclerostin levels correlate with cognitive impairment back in humans, they associated sclerostin levels with cognitive function scores and indeed found a negative correlation. Higher sclerosin levels associated with lower cognitive scores in humans, even after age adjustment, which is remarkable. And perhaps coolest of all, in my opinion, they were then able to show that treating sclerosin mice, treating them with an antibody against sclerosin, basically you have the sclerosin, the antibody binds to it and blocks it from binding to the LRP receptor. Was able to restore and lower amyloid beta levels and improve cognitive function. So that's what you see here in this figure, where pink is the sclerostatin mice, and what you're looking at is amyloid levels across these various figures, and the green is the antibody-treated sclerostatin mice, and what you see is a decrease in the amyloid levels, and there was also improved cognitive function and decreased plaque accumulation, which is all extremely cool. Now, the reason this is so exciting is that a drug that actually works this way called Remosozumab, or Evenity, is already routinely used for osteoporosis. Currently, it's not approved for long-term use, but the idea that this pre-existing bone drug against sclerostin might also benefit the human brain is mind-blowing to me, or I guess mind-preserving in this case. Pardon the pun. Now, I'd mentioned that I'd share something kind of shocking and personal. I've actually been on this drug, Remosozumab, for my own bones. This is because I have an extremely rare mutation that only a few people in the world have in this LRP receptor, which interacts with sclerostin. And that was actually the topic of a case report that I was subject of back in 2019. This is also the reason that I can't run anymore. Because the pathway that sclerosin inhibits in me is less active. At least that's the thought. So my bones don't remodel properly to mechanical stress. So in my history, when I started running, my first year of running, I did great. 3,000-mile year, I was running sub-3-hour marathons. But because my bones couldn't remodel properly, they just got weaker and weaker with more running. And eventually I had to give up marathon running, which kind of sucked. But then I went on various medications, including romosozumab, and my bones got better. Anyway, the point being, I have a personal interest in this connection between bone and brain. And if I could have one wish with respect to my own health now, it would be invincible bones and to avoid Alzheimer's disease. So the fact that these two are linked in this new study to me is absolutely beautiful. And I hope I was able to communicate some of that awe and beauty in science to you in this video.

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