{"entity": "publication", "iuid": "ef3776214c30409e80b6fbbd20eba8bc", "timestamp": "2026-07-05T14:33:55.836Z", "links": {"self": {"href": "https://publications.scilifelab.se/publication/ef3776214c30409e80b6fbbd20eba8bc.json"}, "display": {"href": "https://publications.scilifelab.se/publication/ef3776214c30409e80b6fbbd20eba8bc"}}, "title": "Altered APP trafficking drives amyloidogenic processing in primary neurons from the AppNL-F knock-in mouse model of Alzheimer's disease.", "authors": [{"family": "Yu", "given": "Yang", "initials": "Y"}, {"family": "Zhou", "given": "Robin Ziyue", "initials": "RZ"}, {"family": "Nilsson", "given": "Per", "initials": "P"}, {"family": "Winblad", "given": "Bengt", "initials": "B"}, {"family": "Tjernberg", "given": "Lars O", "initials": "LO"}, {"family": "Schedin-Weiss", "given": "Sophia", "initials": "S"}], "type": "journal article", "published": "2025-11-00", "journal": {"title": "Neurobiol. Dis.", "issn": "1095-953X", "volume": "216", "pages": "107129", "issn-l": "0969-9961"}, "abstract": "Self-assembly of the 42-residue long amyloid \u03b2-peptide (A\u03b242) into neurotoxic aggregates - eventually leading to formation of amyloid plaques - is a key event in Alzheimer's disease (AD) pathogenesis. Still, the intracellular mechanisms leading to A\u03b242 formation and aggregation in neurons are poorly defined. Here, we used the AppNL-F knock-in mouse model to analyze the effect of A\u03b242-induced pathology on the subcellular location of the A\u03b2 precursor protein (APP), its C-terminal fragments (CTFs) and A\u03b242 in primary neurons. Stimulated emission depletion (STED) microscopy was used to obtain super-resolution and enable colocalization analysis. APP/CTF levels were to a high extent found in clathrin-coated vesicles in the perinuclear region in soma in both wild-type and AppNL-F neurons and significantly increased in early endosomes in neurites. In distal axons, increased colocalization of APP/CTF with the synaptic vesicle protein synaptophysin was observed. Western blotting showed a three-fold decrease in mature/immature APP in AppNL-F neurons, and ELISA showed a 2.7 and 7.2-fold increase in intra- and extracellular A\u03b242 levels, respectively. Interestingly, LAMP1-positive vesicles were larger in AppNL-F neurons than in wild-type neurons. Thus, processing of APP and axonal transport of APP/CTFs is increased in AppNL-F neurons, resulting in enhanced levels of the immediate A\u03b2 precursor (CTF\u03b2) at the presynapse. Hence, an increase in CTF\u03b2 levels at sites with high \u03b3-secretase activity leads to increased formation and secretion of A\u03b242. This, in turn, results in enhanced re-uptake of A\u03b242 and enlarged A\u03b242-containing late endosomes/lysosomes in soma, causing toxic downstream effects.", "doi": "10.1016/j.nbd.2025.107129", "pmid": "41027547", "labels": {"Integrated Microscopy Technologies Stockholm": "Service"}, "xrefs": [{"db": "pii", "key": "S0969-9961(25)00346-8"}], "notes": [], "created": "2026-06-23T18:06:06.513Z", "modified": "2026-06-23T18:06:06.517Z"}