{
  "abstract": "Familial Alzheimer's disease (AD) mutations in amyloid precursor protein (APP) alter amyloid-beta secretion profiles, but their effects on neuronal protein and lipid homeostasis remain incompletely understood. To identify early, cell-autonomous phenotypes associated with AD, we used isogenic KOLF2.1J iPSC-derived NGN2 neurons (iNeurons) carrying a heterozygous or homozygous APP-London mutation (V717I) and conducted a longitudinal proteomic study. Results revealed that maturation was the dominant source of proteomic variation, while genotype-dependent effects were pronounced in homozygous APP-London iNeurons. At four weeks, homozygous APP-London iNeurons showed increased APP abundance by proteomics and immunoblot, and increased alpha-CTF signal by immunoblotting. However, alpha-CTF/FL-APP and alpha-CTF/FL-APP ratios from immunoblot did not differ significantly from revertant controls, leaving preferential CTF accumulation unresolved and instead indicating increased steady-state abundance of APP-derived species. Proteomics remodeling in APP-London mutants converged on synaptic, endosomal, and calcium signaling pathways. Notably, homozygous APP-London iNeurons showed a distinct accumulation of cholesterol-biosynthetic enzymes and altered abundance of cholesterol transporters, an increased free/total cellular cholesterol without corresponding induction of SREBP2 target transcripts Pharmacological perturbation of cholesterol metabolism altered A beta 40 and Abeta 42 secretion in a compound-specific manner and produced minimal changes in bulk cellular cholesterol, indicating that A beta secretion was not simply determined by total cholesterol abundance. Finally, we identified SYT4 as a potential gamma-secretase target or associated factor that warrants further validation. These findings identify cholesterol dyshomeostasis as an early metabolic phenotype of iNeurons carrying the APP-London mutation, extending the molecular phenotype beyond altered A beta secretion.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 3,
  "authors": [
    {
      "name": "Jesús Muñoz-Estrada",
      "orcid": "0000-0002-6995-2996"
    },
    {
      "name": "Yuming Jiang",
      "orcid": "0000-0001-7444-3849"
    },
    {
      "name": "Jesse G. Meyer",
      "orcid": "0000-0003-2753-3926"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0hrr8qr5kw24c.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.20.760505",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.20.760505v1.full",
  "id": "0hrr8qr5kw24c",
  "issns": [
    "2692-8205"
  ],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.20.760505v1",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7223476477",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.20.760505v1.full.pdf",
  "pmcid": "PMC13738630",
  "pmid": "42996081",
  "published": "2026-10-20",
  "publisher": "Cold Spring Harbor Laboratory Preprints",
  "ris": "https://research.draconitic.com/paper/0hrr8qr5kw24c.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:29:29Z",
      "native_id": "10.64898/2026.10.20.760505",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.20.760505v1"
    },
    {
      "first_seen": "2026-11-09T12:23:35Z",
      "native_id": "PMC13738630",
      "source": "pmc",
      "url": "https://doi.org/10.64898/2026.10.20.760505"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Temporal Proteomics Links the APP London Mutation to Early Cholesterol Remodeling Cell Programs in Human Neurons",
  "title_text": "Temporal Proteomics Links the APP London Mutation to Early Cholesterol Remodeling Cell Programs in Human Neurons",
  "type": "preprint",
  "updated_at": "2026-11-09T12:23:35Z",
  "url": "https://research.draconitic.com/paper/0hrr8qr5kw24c",
  "venue": "bioRxiv",
  "versions": []
}