Imagine your brain as a library. Each book stacked on the shelves of this humongous, complex, intricately designed library is an individual memory. Strangely, all the books are pretty much within your reach, but then something sinister starts to happen. Slowly and gradually each book starts getting placed on the topmost shelf. You tiptoe and go all out to try grabbing it, but it still stays just out of your reach. Feels extremely frustrating, doesn’t it? It’s as if the book or the memory is still right there but is either inaccessible or hard to retrieve. Dial this struggle up to 11 and you have something called dementia, a disease that strips a person of their memory and their identity at a snail’s pace.
Recently scientists revealed new information regarding dementia, a novel mutation in the genes encoding for a receptor complex called TREM2 – DAP12, with the former already infamous for Alzheimer’s. Before that, let us have a brief rundown of what the TREM2 – DAP12 complex is. TREM2 receptor exists in abundance on cells of myeloid origin (hence expanded as triggering receptors expressed on myeloid cells 2) such as microglia in the central nervous system, osteoclasts in the bone tissue, and Kupffer cells in the liver. Interestingly, all these cells are tissue-specific variants of macrophages, which we will discuss further. TREM2 can bind to lipid molecules such as phospholipids, low-density and high-density lipoproteins, and even apoptotic cells.
All you need to know about DAP12 is that it’s a protein that binds to TREM2 and initiates cell activation.
Further, they uncovered that a mutation in the TREM2 gene causes malfunction of the microglia. In turn, this makes them less adept at clearing off deposits of β- amyloid, the vandal protein that aggregates and accumulates in the brain tissue of an Alzheimer’s victim. This malfunction advances this disease faster in the long run. β- amyloid not only creates a lot of chaos just by its very existence but to add the cherry on top, they also turn the friendly microglia into traitors who start going around wrecking and eating up neurons in the name of “tissue repair”.
Nonetheless, as I said, today’s story is about dementia and not Alzheimer’s and that’s where another such mutational event comes into play. This rare event involves a homozygous mutation (mutation in both copies) in either the TREM2 gene or TYROBP, the gene that codes for DAP12. A new evil rise from this mutation, something that the medical world calls Nasu-Hakola disease – a sort of dementia. Unlike Alzheimer’s which takes its sweet time to consume a person, Nasu-Hakola disease likes to cut to the chase. It starts to manifest as early as adolescence and usually these individuals meet their demise pretty early in life.
Yingyue Zhou and her colleagues used a method called cell clustering, to study the cells involved. In a mixture of cells containing oligodendrocytes, microglia, astrocytes, pericytes, endothelial cells, smooth muscle cells, fibroblasts, and a myriad of other immune cells, they zeroed onto microglia as the completely exclusive expresser of TYROBP, confirming that the ball’s in the court of myeloid cells. But like every sport, you can’t play ball alone and we have teammates here as well. Turns out certain genes were upregulated in almost every cell type mentioned above in that mixture when compared to the control subjects. This explains all types of gliosis observed in the brain of individuals with Nasu-Hakola disease.
Well now that they figured out that microglia were the lead characters, it was time to decipher the script of this show. So, they delved deeper and found upregulated genes in three pathways in microglia: 1. RUNX1 which is responsible for controlling the proliferation of microglia post-injury., 2. STAT3 (which belongs to a well-known signaling pathway called JAK-STAT), is involved in controlling cell adhesion and cytoskeleton activity, things that are necessary for the microglia to move around, and 3. TGFβ which also promotes cell proliferation and differentiation. Ironically these pathways normally govern tissue repair but in the case of Nasu-Hakola disease, were driving the microglia towards a more aggressive, disordered, and destructive phenotype.
Remember we talked about this thing about how pretty much every cell bearing a TREM2 receptor was a variant of macrophage? Well, the Nasu-Hakola disease microglia share their genetic signature quite a lot with IL-10-stimulated macrophages, both have anti-inflammatory and tissue repair pathways activated. A simple experiment was performed to confirm this. They borrowed macrophages from the bone marrow of both wild-type mice and the ones having Nasu-Hakola disease, hence lacking DAP12 signaling. A stressful environment was mimicked and created using certain chemicals, and these macrophages were then allowed to grow there. It wasn’t a surprise when they saw that by adding molecules of IL-10 into this environment, the expression of the STAT3 pathway shot up in the Nasu-Hakola disease macrophages. Flow cytometry experiments confirmed that the Nasu-Hakola disease macrophages had higher amounts of normal and phosphorylated STAT3 molecules than the control subjects, thus validating the fact that the STAT3 pathway starts to spiral out of control when DAP12 is not around anymore to hold it back.
Well, let us not just pin everything on the microglia and let the accomplices get off scot-free.
The researchers observed that there was significant gene upregulation in pericytes and endothelial cells as compared to control subjects. Pericytes are cells that structure the blood vessels in the CNS. They also secrete extracellular matrices such as collagen which helps regulate the permeability and the contraction exhibited by the vessels. It was observed that pericytes in Nasu-Hakola patients produced exorbitant amounts of phosphodiesterase, which are enzymes that help pericytes contract, compared to wild-type subjects. Additionally, these dysfunctional pericytes were also producing excessive amounts of ECM. Both abnormal conditions erratically narrow the blood vessels and thicken them, in a way, choking them.
Now it’s the turn of astrocytes to come under the spotlight. In these supporting cells, genes that governed responses to tissue injury, remodeling, and wound healing had been upregulated. Among all the several upregulated genes, this one gene called GFAP was found to be common in Nasu-Hakola disease, Alzheimer’s, and Multiple Sclerosis. Although the function of GFAP is theorized to help maintain the mechanical strength of astrocytes, it’s still poorly understood. Hence being continuous with the narrative, GFAP was seemingly being expressed more in Nasu-Hakola diseased astrocytes compared to control.
Also, intensive demyelination of neurons was seen in Nasu-Hakola disease brain tissue which points fingers toward oligodendrocytes. Gene expression analysis displays the downregulation of genes in oligodendrocytes that code for the building blocks of myelin, which justifies the demyelination.
Now, since Nasu-Hakola disease is neurodegenerative, the researchers had to give a shot at studying the activity of the neurons. As anticipated, there was a downregulation of genes in the excitatory and inhibitory neurons which meant only one thing – loss of neuronal activity. The expression of ribosomal genes had also diminished, which meant diminished protein synthesis. Also, the Nasu-Hakola disease neurons had a hard time communicating with each other since the genes responsible for synaptic transmission had also nosedived in expression.
Dementia is one of the scariest symptoms of all the progressive diseases out there (at least in my opinion). Imagine waking up every day to the fact that eventually, you’ll lose your memories, bit by bit, of not just your own identity but also those of your loved ones, and there’s absolutely nothing you can do about it, but wait, till there’s nothing left anymore, only a ghost of your former self. You see if Alzheimer’s was a tree, dementia would be the trunk of it, the most visceral part. And chopping this trunk with the right tool could easily bring down the entire tree in a single swoop. One such strategy could be bringing a sidetracked STAT3 activation back to normal using inhibitors of the JAK-STAT pathway. This would not only help restore stasis but also “might ” just help hit the brakes on this slow and torturing ride into the oblivion of forgetfulness.
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Article author: Lalit Anand. Lalit is a Biotechnology major at the Vellore Institute of Technology. He loves reading about the immune system and its peculiar interactions with other bodily systems.
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