🧬 biology

Reduced LACTB expression in myeloid cells is associated with elevated succinylcarnitine and reduced Alzheimer’s disease risk

This study demonstrates that reduced LACTB expression in myeloid cells lowers Alzheimer's disease risk by increasing succinylcarnitine levels and enhancing oxidative phosphorylation, positioning LACTB as a promising inflammation-responsive therapeutic target for the disease.

Original authors: Alison Goate, Carmen Romero-Molina, Ruben Gomez-Gutierrez, Wen Yi See, Tulsi Patel, Hayk Davtyan, Jiacheng Ma, Quanyun Xu, Michael Sewell, Kendra Allton, Morgan McReynolds, Olivia Calderon, Yaima Ligh

Published 2026-07-13

📖 5 min read🧠 Deep dive

CC BY 4.0

Original authors: Alison Goate, Carmen Romero-Molina, Ruben Gomez-Gutierrez, Wen Yi See, Tulsi Patel, Hayk Davtyan, Jiacheng Ma, Quanyun Xu, Michael Sewell, Kendra Allton, Morgan McReynolds, Olivia Calderon, Yaima Lightfoot, Guido Bommer, Carlos Cruchaga, Mathew Blurton-Jones, William Ray, Edoardo Marcora

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ⚕️ This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer

Imagine your brain is a bustling city, and the microglia are the sanitation crew. Their job is to sweep up trash, clear out debris, and keep the streets clean. In Alzheimer's disease, this crew sometimes gets overwhelmed, the streets get clogged with sticky "amyloid plaques," and the city starts to crumble.

For a long time, scientists have been looking for a way to make this sanitation crew work better. A new study has found a very specific switch inside these cells that, when turned down, actually helps the city stay cleaner and safer. That switch is a protein called LACTB.

Here's the twist: The study suggests that having less LACTB is actually a good thing for fighting Alzheimer's.

The "Succinylcarnitine" Mystery

Inside the sanitation crew's trucks (the cells), there's a tiny chemical called succinylcarnitine. Think of this chemical like a special fuel additive. Scientists have noticed that when people have high levels of this fuel in their brain fluid, they are less likely to get Alzheimer's.

But where does this fuel come from? The study found that LACTB is a primary enzyme responsible for breaking down succinylcarnitine.

High LACTB: The shredder is working, breaking down the fuel. The city runs lower on succinylcarnitine.
Low LACTB: The shredder is slow or broken. The fuel (succinylcarnitine) builds up.

The researchers used a powerful statistical tool called Mendelian randomization (which is like looking at a family tree to see how genes naturally affect health) to show a clear path: People who naturally have lower LACTB levels in their immune cells tend to have higher levels of succinylcarnitine, and this combination is linked to a lower risk of Alzheimer's.

The Shredder's Secret Job

To prove this wasn't just a coincidence, the team went into the lab. They created "shredder-less" versions of human immune cells (both macrophages and microglia).

The Result: When they removed LACTB, the cells immediately started hoarding succinylcarnitine.
The Proof: They even built a tiny machine using just the LACTB protein and a special glowing version of the fuel. When they mixed them, the LACTB protein literally chewed up the fuel. This confirmed that LACTB is indeed a primary enzyme responsible for breaking it down.

What Happens When the Shredder is Off?

When the researchers turned off the LACTB shredder in these cells, the cells didn't just hold onto more fuel; they changed how they worked entirely.

Supercharged Engines: The cells switched to a more efficient energy mode called oxidative phosphorylation. It's like the sanitation crew swapped their old, gas-guzzling trucks for high-efficiency electric ones. They could do more work with less waste.
Slower Factory: The cells slowed down their protein-making factories. Instead of churning out bulk materials, they focused their energy on cleaning and defense.
Closer Association: When the cells were challenged with inflammation (like a city under attack), the "LACTB-less" cells showed an increased association with the amyloid plaques. In a test where they put these human cells into mice with Alzheimer's-like brains, the cells without LACTB clustered around the plaques more tightly, acting like a dedicated cleanup crew.

The "On-Off" Switch

Interestingly, the study found that when the immune system gets a signal to fight (from chemicals called interferon or TNF), the body naturally turns up the LACTB shredder. This suggests that during an infection, the body wants to break down that fuel. But in the context of Alzheimer's, having that shredder turned down seems to be the protective factor.

What the Study Does NOT Say

It's important to know what this study doesn't claim:

It doesn't say LACTB is the only cause: The study focuses on the immune cells, but other factors still play a role in Alzheimer's.
It doesn't say the mice were "cured": In the mouse experiments, the LACTB-less cells didn't completely erase the plaques. They just hung around them more and showed signs of being more active. The amount of plaque didn't change drastically, but the behavior of the cleanup crew did.
It doesn't say we should stop making LACTB entirely: The study suggests that reduced expression is protective, but it doesn't claim that having zero LACTB is perfect or that we should try to eliminate it from the body right now.

The Big Picture

The researchers suggest that LACTB is a promising target for new drugs. Because we know exactly what it does (it breaks down succinylcarnitine) and we can measure the fuel levels in blood or spinal fluid, we could potentially develop a drug that gently slows down the LACTB shredder. This would let the "fuel" build up, supercharge the brain's sanitation crew, and perhaps help keep the city of the brain clean for longer.

The study concludes that while we have a lot of work to do, we have found a very specific, measurable, and potentially "druggable" lever to pull in the fight against Alzheimer's.

Technical Summary: Reduced LACTB Expression in Myeloid Cells is Associated with Elevated Succinylcarnitine and Reduced Alzheimer's Disease Risk

Problem Statement
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid plaques, neurofibrillary tangles, and neuroinflammation. While genetic studies have consistently implicated myeloid cells (specifically microglia) in AD etiology, the functional mechanisms linking specific genetic risk loci to disease pathology remain unclear. The LACTB gene (Lactamase β), located within a well-established AD risk locus on chromosome 15q22, has been genetically associated with AD susceptibility, obesity, and metabolic traits. However, its specific function in myeloid cells, its enzymatic activity, and its causal relationship to AD risk and metabolite profiles had not been experimentally validated. Furthermore, the role of succinylcarnitine, a metabolite genetically linked to LACTB loss-of-function and independently associated with lower AD risk, required mechanistic elucidation.

Methodology
The study employed a multi-modal approach integrating human genetics, in vitro cellular models, and in vivo xenotransplantation:

Mendelian Randomization (MR): The authors performed two-sample MR analyses integrating AD genome-wide association study (GWAS) data with myeloid expression quantitative trait loci (eQTLs) and cerebrospinal fluid (CSF) metabolite quantitative trait loci (mQTLs) to assess causal relationships between LACTB expression, succinylcarnitine levels, and AD risk.
Cellular Models:
- Human Macrophages: THP1 monocytes were differentiated into macrophages and subjected to LACTB knock-down (KD) via siRNA.
- Human Microglia: Isogenic LACTB knock-out (KO) and wild-type (WT) microglia were derived from WTC11 induced pluripotent stem cells (iPSCs) using CRISPR-Cas9.
- Enzymatic Assays: Recombinant human LACTB protein was purified to test direct cleavage of succinylcarnitine. Isotope tracing with $^{13}$ C-labeled succinylcarnitine was used to track metabolic fate.
- Post-Translational Modification: HEK cells and macrophages were treated with diethyl succinate to induce succinylation, followed by immunoprecipitation to assess LACTB succinylation and activity.
Transcriptomics and Functional Assays: Bulk and single-cell RNA sequencing (scRNA-seq) were performed on KD/KO cells to identify pathway alterations. Functional assays included Seahorse metabolic profiling (oxidative phosphorylation), protein synthesis measurement (Click-iT AHA), lipidomics, and efferocytosis assays (myelin phagocytosis, lysosomal activity) under inflammatory stimulation (IFN/TNF).
In Vivo Xenotransplantation: Human WT and LACTB KO microglia precursors were transplanted into newborn hCSF1-5xFAD mice (a model of amyloid deposition). Mice were analyzed at 6 months for microglia engraftment, metabolic profiles, amyloid plaque burden, and microglia activation markers.

Key Contributions and Results

Genetic Causality: MR analyses revealed that genetically predicted lower LACTB expression in myeloid cells is causally associated with reduced AD risk and higher CSF succinylcarnitine levels. Conversely, higher succinylcarnitine levels are associated with lower AD risk.
Enzymatic Function: The study identified LACTB as a primary enzyme responsible for the hydrolysis of succinylcarnitine into carnitine and succinate. LACTB KD/KO in human macrophages and microglia, as well as in enzymatically-dead (ED) mouse models, resulted in significantly elevated succinylcarnitine levels.
Regulatory Feedback: The authors demonstrated that LACTB activity is inhibited by its own succinylation. Treatment with diethyl succinate induced LACTB succinylation, which reduced its enzymatic cleavage of succinyl-D-aspartate and increased intracellular succinylcarnitine, suggesting a negative feedback loop.
Transcriptional and Metabolic Reprogramming:
- Metabolism: LACTB loss increased oxidative phosphorylation (OXPHOS) capacity but reduced nascent protein synthesis and triacylglyceride (TG) levels.
- Immune Response: LACTB expression was upregulated by IFN and TNF stimulation. LACTB KD/KO altered the transcriptional response to these cytokines, specifically affecting genes related to antigen presentation and pro-inflammatory cytokines (e.g., IL1B, CCL3).
- Efferocytosis: Under inflammatory conditions, LACTB KD/KO reduced myelin phagocytosis and lysosomal acidification/proteolytic capacity in both macrophages and microglia.
In Vivo Phenotype: In the 5xFAD mouse model, xenotransplanted human LACTB KO microglia showed:
- Increased clustering around amyloid plaques compared to WT.
- A mild reduction in amyloid plaque area and number.
- Increased expression of activation markers (CD9, LGALS3) and antigen presentation markers (HLA-DRB1).
- Metabolic alterations including increased acetyl-CoA and decreased carnitine species.

Significance and Claims
The paper claims to experimentally validate the genetic association between reduced LACTB expression in myeloid cells and reduced AD risk. It establishes a causal mechanistic link where lower LACTB leads to elevated succinylcarnitine, a metabolite associated with protection against AD. The authors propose that LACTB acts as an inflammation-responsive regulator of myeloid cell metabolism and function.

By shifting energy away from bulk protein synthesis and lipid storage toward high OXPHOS, LACTB reduction may promote a bioenergetically efficient state that supports microglial function and counters the metabolic exhaustion observed in AD. The study highlights LACTB as a promising therapeutic target due to its structural characterization as a serine hydrolase and the availability of small-molecule inhibitors for its bacterial orthologs. Furthermore, the authors identify succinylcarnitine as a genetically validated endophenotype and a potential pharmacodynamic biomarker for target engagement, enhancing the translational tractability of LACTB inhibition strategies for AD.