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Here, we demonstrate that amyloid precursor protein (APP) processing in cortical neurons is disrupted upon loss of Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), the NAD\u207a-synthesizing enzyme in neurons, resulting in accumulation of APP C-terminal fragments (APP-CTFs). Knockdown (KD) of the NAD\u207a hydrolase sterile alpha and TIR motif-containing protein 1 (SARM1) restores APP-CTF levels in NMNAT2 knockout (KO) neurons to wild-type levels, whereas NAD\u207a supplementation yields modest rescue. Redox profiling indicates that NMNAT2 loss reduces NAD\u207a\/NADH redox potential when APP-CTF starts accumulating. Seahorse metabolic flux analysis shows that NMNAT2 deficiency induces early glycolytic impairment, followed by deficits in mitochondrial respiration. Notably, SARM1 KD, but not NAD\u207a supplementation, rescues mitochondrial function in NMNAT2 KO neurons. Temporal profiling of NMNAT2 KO neurons revealed a biphasic pattern in APP-CTF accumulation, with an initial gradual increase followed by a marked acceleration, paralleling the transition from an initially small number to a substantially greater number of differentially expressed proteins. Pathway enrichment analysis of proteomic changes suggests JNK\/MAPK signaling is upregulated in the early phase, with late-phase downregulation of mitochondrial function and upregulation of endoplasmic reticulum stress and unfolded protein response pathways. Collectively, these findings demonstrate that neuronal NAD\u207a depletion drives a progressive, SARM1-dependent disruption of redox homeostasis and proteostasis, resulting in impaired APP processing. The NMNAT2\u2013SARM1 axis emerges as a critical pathway linking metabolic stress to proteinopathy, positioning SARM1 as a key mediator of neurodegenerative dysfunction.<\/jats:p>","DOI":"10.64898\/2026.04.16.718990","type":"posted-content","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T15:35:12Z","timestamp":1776785712000},"source":"Crossref","is-referenced-by-count":0,"title":["NMNAT2-SARM1 Axis Drives Redox Failure and Disrupts APP Processing in Neurons"],"prefix":"10.64898","author":[{"given":"Andrea","family":"Enriquez","sequence":"first","affiliation":[{"name":"Gill Institute for Neuroscience, Indiana University, Bloomington, USA"},{"name":"Program in Neuroscience, Indiana University, Bloomington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sen","family":"Yang","sequence":"additional","affiliation":[{"name":"Gill Institute for Neuroscience, Indiana University, Bloomington, USA"},{"name":"Program in Neuroscience, Indiana University, Bloomington, USA"},{"name":"Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen","family":"Ling","sequence":"additional","affiliation":[{"name":"Neuroscience Drug Discovery, Ionis Pharmaceuticals, Inc., 2855, Gazelle Court, Carlsbad, CA 92010 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paymaan","family":"Jafar-Nejad","sequence":"additional","affiliation":[{"name":"Neuroscience Drug Discovery, Ionis Pharmaceuticals, Inc., 2855, Gazelle Court, Carlsbad, CA 92010 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui-Chen","family":"Lu","sequence":"additional","affiliation":[{"name":"Gill Institute for Neuroscience, Indiana University, Bloomington, USA"},{"name":"Program in Neuroscience, Indiana University, Bloomington, USA"},{"name":"Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026042413550524000_2026.04.16.718990v1.1","doi-asserted-by":"publisher","DOI":"10.2478\/jtim-2022-0024"},{"key":"2026042413550524000_2026.04.16.718990v1.2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1427.007"},{"key":"2026042413550524000_2026.04.16.718990v1.3","doi-asserted-by":"crossref","unstructured":"Watanabe H , Shima S , Kawabata K , Mizutani Y , Ueda A , Ito M . 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