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Neurodegenerative NMNAT2 Deficiency Promotes APP Processing in a SARM1-Dependent Manner.

Andrea Enriquez1,2, Sen Yang1,2,3, Karen Ling4

  • 1Gill Institute for Neuroscience, Indiana University, Bloomington, IN 47405, USA.

Cells
|June 25, 2026
PubMed
Summary
This summary is machine-generated.

Loss of NMNAT2 enzyme impairs neuronal NAD+ synthesis, disrupting amyloid precursor protein processing and causing neurodegeneration. SARM1 mediates this metabolic stress and proteinopathy.

Keywords:
APP processingNAD+ metabolismNMNAT2SARM1proteostasis

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Area of Science:

  • Neuroscience
  • Cell Biology
  • Metabolic Disorders

Background:

  • Metabolic dysfunction and proteinopathy characterize neurodegenerative diseases.
  • The interplay between these processes is not well understood.

Purpose of the Study:

  • To investigate the mechanistic link between Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) deficiency, metabolic disruption, and proteinopathy in neurons.
  • To identify key mediators in this pathway.

Main Methods:

  • Utilized NMNAT2 knockout cortical neurons.
  • Performed temporal profiling of APP C-terminal fragments (APP-CTFs) and protein expression.
  • Conducted pathway and Seahorse analyses.
  • Investigated the role of sterile alpha and TIR motif-containing protein 1 (SARM1) and NAD+ supplementation.

Main Results:

  • NMNAT2 loss disrupted APP processing, increasing APP-CTFs and lowering the NAD+/NADH ratio.
  • Observed biphasic APP-CTF accumulation, early JNK/MAPK activation, and late mitochondrial dysfunction.
  • Identified early glycolytic impairment followed by respiratory deficits.
  • SARM1 knockdown rescued mitochondrial function and normalized APP-CTF levels, outperforming NAD+ supplementation.

Conclusions:

  • Neuronal NAD+ depletion drives SARM1-dependent metabolic and proteostasis disruption, impairing APP processing.
  • The NMNAT2-SARM1 axis links metabolic stress to proteinopathy, with SARM1 as a key mediator in neurodegeneration.