Had a great time visiting @tcddublin.bsky.social last week where I got to share some of our new work from the lab! 🧠
Really enjoyed the discussions and meeting many amazing researchers, including some old friends 😊
Thanks to @David Loane and the TCD Biochemical society for the lovely invitation

Thrilled to be at #ADPD2025 in Vienna ☀️
Thanks to everyone who came to our session on innate immunity yesterday! Really enjoyed the discussions after on our findings on #metabolism & #microglia function in #alzheimer’s disease
I’ve learned a lot at this meeting - looking forward to Copenhagen 2026 🧠

This month the McManus lab turns 1! 🎉

It’s been an amazing year, from starting out with an empty lab space to having our first co-authorships, grant awards and successful student projects 📄

Delighted to work with such a wonderful team of scientists on #alzheimersdisease and #dementia research 🧠

Happy St Patrick’s Day!
And what a lovely surprise from the lab, who all wore green this morning ☺️☘️

This work highlights #NLRP3 inhibition as an important therapeutic target in #dementia, by not only blocking inflammation but also reprogramming the cells on a metabolic and epigenetic level (18)

We then tested a NLRP3 inhibitor that could cross into the brain. NLRP3 inhibition reduced inflammasome activation and reprogrammed microglia to increase Abeta uptake, which was driven by SLC1A3+ microglia (17)

In contrast, inhibiting JMJD3 reduced Slc1a3 mRNA, and the NLRP3-/- microglia were no longer metabolically efficient nor could they phagocytosis Abeta. aKG could not rescue this effect, confirming it was acting on the same part of the pathway (16)

aKG is also an important co-factor for enzymes that modify the epigenetic landscape e.g. JMJD3. In line with this, we found the Slc1a3 gene region was more open and active in NLRP3-/- microglia (15)

NLRP3 inhibition could mimic the genetic knock out, but only when used over many days. Interestingly the inhibitor-induced metabolic changes including increased aKG occurred upstream of gene transcription and phagocytic changes (14)

In the scRNAseq, metabolism and phagocytosis were connected. Functionally the increased phagocytosis in the NLRP3-/- microglia was lost, when cells were deprived of glutamine or glutamate (via SLC1A3 inhibition). However aKG could rescue this (13)

By tracing glutamine utilisation, we observed that NLRP3-/- cells preferred to use glutamine to produce the metabolite alpha-ketoglutarate (aKG) and the concentration of aKG (downstream of glutamate) was also increased (12)

At a functional level, NLRP3-/- microglia had increased mitochondrial activity and respiration (oxygen consumption rate – OCR) (11)

In contrast, in post mortem brain tissue of those with #Alzheimer’s disease who have inflammasome activation in their brain, we found reduced levels of SLC1A3 which was expressed in both microglia and astrocytes (10)

At a protein level, we observed that microglia express SLC1A3 intracellularly, and the amount was increased in NLRP3-/- cells and cortex (9)

SLC1A3 is well characterised on astrocytes. To verify the expression changes we performed bulk RNAseq on different NLRP3-/- microglia ex vivo and again saw an increase in microglial Slc1a3 (8)

To uncover what was driving this, we did single cell RNAseq. This unveiled a population of NLRP3-/- microglia with a strong metabolic and phagocytic signature, and the most significantly changed gene was the glutamate transporter Slc1a3 (7)

A thread on our main findings:
During my postdoc I noticed something surprising, where NLRP3-/- microglia were much better at #phagocytosis than wild-type cells even under basal (unstimulated) conditions (6)