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Here, we show that loss of the neuronal NAD+-synthesizing enzyme Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) disrupts amyloid precursor protein (APP) processing in cortical neurons, leading to accumulation of APP C-terminal fragments (APP-CTFs). NMNAT2 deficiency lowers the NAD+\/NADH redox ratio coincident with APP-CTF buildup. Temporal profiling reveals a biphasic increase in APP-CTFs, with an initial gradual rise followed by rapid accumulation, paralleling the expansion of differentially expressed proteins. Pathway analysis indicates early activation of JNK\/MAPK signaling, followed by late-stage suppression of mitochondrial pathways and induction of endoplasmic reticulum stress and unfolded protein response programs. Seahorse analyses reveal early glycolytic impairment followed by deficits in mitochondrial respiration. Knockdown of the NAD+ hydrolase sterile alpha and TIR motif-containing protein 1 (SARM1) restores mitochondrial function and normalizes APP-CTF levels in NMNAT2 knockout neurons, whereas NAD+ supplementation provides only modest rescue. Together, these data demonstrate that neuronal NAD+ depletion drives progressive, SARM1-dependent disruption of glucose metabolism and proteostasis, impairing APP processing. The NMNAT2\u2013SARM1 axis thus links metabolic stress to proteinopathy and highlights SARM1 as a central mediator of neurodegenerative dysfunction.<\/jats:p>","DOI":"10.3390\/cells15121100","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T10:19:53Z","timestamp":1781691593000},"page":"1100","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neurodegenerative NMNAT2 Deficiency Promotes APP Processing in a SARM1-Dependent Manner"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9236-6707","authenticated-orcid":false,"given":"Andrea","family":"Enriquez","sequence":"first","affiliation":[{"name":"Gill Institute for Neuroscience, Indiana University, Bloomington, IN 47405, USA"},{"name":"Program in Neuroscience, Indiana University, Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4140-3160","authenticated-orcid":false,"given":"Sen","family":"Yang","sequence":"additional","affiliation":[{"name":"Gill Institute for Neuroscience, Indiana University, Bloomington, IN 47405, USA"},{"name":"Program in Neuroscience, Indiana University, Bloomington, IN 47405, USA"},{"name":"Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Ling","sequence":"additional","affiliation":[{"name":"Neuroscience Drug Discovery, IONIS Pharmaceuticals Inc., Carlsbad, CA 92010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paymaan","family":"Jafar-Nejad","sequence":"additional","affiliation":[{"name":"Neuroscience Drug Discovery, IONIS Pharmaceuticals Inc., Carlsbad, CA 92010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6628-7177","authenticated-orcid":false,"given":"Hui-Chen","family":"Lu","sequence":"additional","affiliation":[{"name":"Gill Institute for Neuroscience, Indiana University, Bloomington, IN 47405, USA"},{"name":"Program in Neuroscience, Indiana University, Bloomington, IN 47405, USA"},{"name":"Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"197","DOI":"10.2478\/jtim-2022-0024","article-title":"Aberrant Energy Metabolism in Alzheimer\u2019s Disease","volume":"10","author":"Yu","year":"2022","journal-title":"J. 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