OPTOGENETICS. APP/PSEN1 MODEL EXTRAPOLATION. IMMUNE SYSTEM ACTIVATION. A SIMPLE TREATMENT THAT WILL TOTALLY BE ON SHELVES IN WALGREENS WITHIN A YEAR. ALL ABOARD CHOO CHOO!!! Is the paper out? that is kind of a wild result. What was the optogenetics targeting? I'm assuming the neurons responsible for the gamma rhythm, and the microglia activation was unintentional, and that's why the decided to attempt the effect with an external light source? Had no one seen that before? Optogenetics and EEG stuff was never on my plate, so I have only a cursory understanding.
Yes, high potential for either breakthrough or years of pseudoscience to come out of this. Much excitement. Wow! They're looking at others models now, but I'm probably not supposed to share that until it's at least being presented publicly. Yep. Optogenetics targetted parvalbumin interneuron and did not show an effect in excitatory neurons (PV-Cre vs. αCamKII-Cre in fig 1) or at non-40 Hz pulses. Why the microglia get activated is anyone's guess / for follow-up work to determine. The light source was used after the optogenetics experiments showed an effect because, as one prof put it: "We're more than a decade away from optogenetic therapies in humans". Note they switch the explanation from "hippocampus" to "visual cortex" when they explain that in the video though. In theory, any signal that gets a stimulus at 40 Hz to the hippocampus should be effective, but not all circuits from the eyes / ears / mouth / fingers / nose are as direct. The closest is deep brain stimulation for Parkinson's, which sort of works okay but isn't very well understood. This is the first (mouse) therapy of the sort, and the first that I know of that links dysregulated signaling to stimulation to targeted activation of certain cells in a certain region to actual non-invasive therapy.OPTOGENETICS. APP/PSEN1 MODEL EXTRAPOLATION. IMMUNE SYSTEM ACTIVATION. A SIMPLE TREATMENT THAT WILL TOTALLY BE ON SHELVES IN WALGREENS WITHIN A YEAR.
Is the paper out? that is kind of a wild result. What was the optogenetics targeting? I'm assuming the neurons responsible for the gamma rhythm, and the microglia activation was unintentional, and that's why the decided to attempt the effect with an external light source?
Had no one seen that before? Optogenetics and EEG stuff was never on my plate, so I have only a cursory understanding.
Oh, sorry for the confusion, I just meant that the FA models upregulate PSEN1 as well (right?). I was referring to the microglia activation, but you def answered my question and more. Yeah, I def want to see this paper. As much as I remember, microglia activation around AD plaques was nothing new, even without external stimulation, but the relevance here is early induction, which can be a can of worms. Wild shit, and hopefully there is some clinical relevance to it.Had no one seen that before?
Note they switch the explanation from "hippocampus" to "visual cortex" when they explain that in the video though. In theory, any signal that gets a stimulus at 40 Hz to the hippocampus should be effective, but not all circuits from the eyes / ears / mouth / fingers / nose are as direct.
Yep yep, realized that after replying and ninja edited. Microglial "activation" is sort of a misnomer in my opinion. But basically they show a state switch. Whether this is a response to less inflammatory factors secreted by neurons, improved blood flow to the area, magic electrical effects, decrease plaque production, etc is not well understood. They characterize in the paper that there is a state change (morphological, RNA expression), but not how / why. There's some thought that microglia have 2+ states, a "pro-inflammatory" / "M1" state and an "neuroregenerative" / "M2" state, but in my opinion that's probably a baloney pigeonhole of what's actually going on. Indeed, though what'll probably not be mentioned in the press releases is "Extended Data Figure 5: A 40 Hz light flicker does not affect Aβ levels in hippocampus or barrel cortex." ... There is still a lot of work to be done.I was referring to the microglia activation, but you def answered my question and more.
Wild shit, and hopefully there is some clinical relevance to it.
The M1/M2 thing is still used as a shorthand to describe aggregate cell behavior when simplicity of explanation is desirable, but is really not taken seriously anymore with regard to single cells. That is, there's a lot of evidence that while certain groups of proteins are more likely to promote inflammation and certain groups to suppress it/promote regeneration, there's too much overlap in any given cell to say that this cell is an "M1" or "M2" cell. The functional ambiguity of the microglia is fascinating, and I've been putting a lot of my effort there recently. I'm becoming more and more convinced that some regenerative therapies that our lab has developed act on the microglia as the most upstream event. That might be crackpot, on the other hand.
For sure, I've just seen a couple talks / papers now that describe some (non-cytokine) receptor as being the thing that polarizes cells in one direction or the other and I find it somewhat garbage science, at least in the Alzheimer's field. Especially since there does't seem to be any real consensus on how they're defined. The microglia you're talking about in this context are with regards to young blood treatments?
Not exactly. My work focuses on the use of mesenchymal cells to treat brain injuries, primarily stroke. Recently we've been using the exosomes that the MSCs spit out as a proxy for MSC therapy. Exosomes appear to promote recovery in rodents and primates just as effectively as the parent cells themselves. Cell targeting is a difficult thing to pin down, because being ~50-100nm, exosomes are difficult to tag and track with any real precision. To the extent we have been able to track them, they seem to target the microglia in the vicinity of the lesion more than any other cell type. Been doing some mechanistic studies recently trying to probe what exactly the effect of "feeding" exosomes from MSC to microglia is. The "young blood" thing (really young bone marrow) is a side business that sprang out of work that mk and I have done together for many years.