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Basic Science and Pathogenesis.

Carmen Romero Molina1,2, Wen Yi See1,2, Ruben Gomez-Gutierrez3

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Summary
This summary is machine-generated.

Lower expression of LACTB and LACTB2 protects against Alzheimer's disease (AD). Reduced LACTB/B2 in myeloid cells impacts mitochondrial respiration and lipid metabolism, suggesting potential as a therapeutic target and biomarker for AD.

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Area of Science:

  • Immunometabolism
  • Neurodegenerative Diseases
  • Genetics

Background:

  • The role of immunometabolism in Alzheimer's Disease (AD) pathogenesis is under investigation.
  • Genetic analysis indicates lower expression of LACTB and LACTB2 is protective against AD.
  • LACTB influences mitochondrial bioenergetics and is linked to AD risk metabolite succinyl-carnitine; LACTB2 modulates mitochondrial mRNA and mitophagy.

Purpose of the Study:

  • To validate the association between LACTB/B2 expression and AD risk.
  • To elucidate the underlying molecular mechanisms of LACTB/B2 in myeloid cells.

Main Methods:

  • Generated LACTB/B2 knockdown (KD) and knockout (KO) myeloid cells (THP1 macrophages, iPSC-derived microglia).
  • Conducted functional assays (migration, phagocytosis, respiration, lysosomal activity, lipid droplets).
  • Performed bulk and single-cell RNA sequencing, metabolomics, and lipidomics.
  • Xenotransplanted human microglia into 5xFAD mouse models.

Main Results:

  • LACTB expression increases during myeloid cell differentiation and stimulation.
  • LACTB KD/KO elevates succinyl-carnitine, enhances oxidative phosphorylation, and upregulates interferon response.
  • Single-cell analysis links high LACTB expression to TNF+ microglia; lipidomics reveals altered ceramides and acyl glycerides.
  • Xenotransplantation of LACTB KO microglia into 5xFAD mice reduced amyloid pathology and increased microglia activation.

Conclusions:

  • LACTB impacts myeloid cell differentiation and response by modulating mitochondrial respiration and lipid metabolism.
  • Reduced LACTB expression is protective in AD, and succinyl-carnitine may serve as a biomarker.
  • LACTB represents a promising therapeutic target for Alzheimer's Disease.