{
  "id": 16331039,
  "title": "Temporal Proteomics Links the APP London Mutation to Early Cholesterol Remodeling Cell Programs in Human Neurons",
  "url": "https://urgent.news/2026/10/24/temporal-proteomics-links-the-app-london-mutation-to-early",
  "topic": "tech",
  "section": "Tech",
  "published": "2026-10-24T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.10.20.760505v1?rss=1"
  },
  "original_language": "en",
  "account": "A recent study unveils how familial Alzheimer's disease (AD) mutations in amyloid precursor protein (APP) impact early neuronal protein and lipid homeostasis. Isogenic KOLF2.1J iPSC-derived neurons were engineered with a heterozygous or homozygous APP-London mutation (V717I) for a comprehensive proteomic analysis. The results showed that maturation primarily drove proteomic variation, while genotype-dependent effects were more pronounced in homozygous APP-London neurons.\n\nAt four weeks, homozygous APP-London neurons displayed higher APP levels and increased alpha-CTF signal via immunoblot analysis. However, the ratio of alpha-CTF to FL-APP did not differ significantly from control neurons, suggesting an accumulation of APP-derived species. The proteomic remodeling in APP-London mutants primarily affected synaptic, endosomal, and calcium signaling pathways.\n\nRemarkably, homozygous APP-London neurons exhibited a distinct buildup of cholesterol-biosynthetic enzymes and altered cholesterol transporter abundance. These neurons also showed increased free/total cellular cholesterol levels without significant changes in bulk cellular cholesterol or induction of SREBP2 target transcripts. Pharmacological intervention in cholesterol metabolism affected A beta 40 and Abeta 42 secretion in a compound-specific manner, but had minimal impact on overall cellular cholesterol levels.\n\nThe study identified SYT4 as a potential gamma-secretase target or associated factor, warranting further investigation. The findings highlight cholesterol dyshomeostasis as an early metabolic phenotype in neurons carrying the APP-London mutation, expanding the molecular phenotype beyond altered A beta secretion.",
  "summary": "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…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 1,
    "also_reported_by": []
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}