Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis

Mitochondrial dysfunction is a well-established hallmark of Alzheimer’s disease (AD), particularly in the context of amyloid-beta (Aβ) accumulation. Here, we explored the progression of mitochondrial impairment associated with cerebral amyloidosis in human and rodent systems expressing AD-relevant APP mutations. We investigated mitochondrial function, dynamics, and degradation in human neural progenitor cells differentiated for two and six weeks, carrying the APP (Swedish/London) mutations. These analyses were complemented by studies in 3- and 9-month-old McGill-R-Thy1-APP transgenic (Tg) rats expressing the APP (Swedish/Indiana) mutations. We observed a consistent accumulation of pathogenic Aβ species associated with mitochondrial damage. In vitro , early indicators of oxidative stress and initial alterations in mitochondrial network dynamics were evident, including increased mitochondrial reactive oxygen species and elevated total DRP1 levels. Later, after 6 weeks of differentiation, significant mitochondrial dysfunction emerged, including reduced membrane potential, increased mitochondrial network fragmentation, and decreased GSH/GSSG ratio. Mitophagy was also disrupted, as evidenced by reduced localization of TOMM20 to the lysosomes, suggesting impaired mitochondrial clearance. Similarly, hippocampal mitochondria fraction of 9-month-old Tg rats showed elevated fission markers, nitrosative stress, and mitochondrial p62 accumulation, which were absent in 3-month-old Tg animals. Hence, we identified both early and late molecular alterations in mitochondrial homeostasis revealing accumulation of mitochondrial stress, altered dynamics, and mitophagy failure in response to sustained Aβ release. Our results underscore mitochondrial vulnerability during early amyloidosis, identifying it as a potential therapeutic target at initial disease stages. It also reinforces the utility of in vitro models for studying cerebral amyloid pathologies. • Mitochondrial homeostasis is affected in APP-mutant human neurons and rat brains • Early mitochondrial stress appears in human and rat amyloidosis models • Sustained Aβ production is linked to mitochondrial damage and disrupted dynamics • Mitochondrial impairment in human and rodent models aligns with pathogenic Aβ • Early mitochondrial vulnerability is a potential therapeutic target in amyloidosis

Schlagwörter

Fachgebiet (DDC)

610 - Medizin und Gesundheit

Projekt

Veranstaltung

Startdatum der Ausstellung

Enddatum der Ausstellung

Startdatum der Konferenz

Enddatum der Konferenz

Datum der letzten Prüfung

ISBN

ISSN

0197-4580
1558-1497

Sprache

Englisch

Während FHNW Zugehörigkeit erstellt

Ja

Zukunftsfelder FHNW

Publikationsstatus

Veröffentlicht

Begutachtung

peer-reviewed

Open Access-Status

Hybrid

Lizenz

Zitation

Motamed, Z., Novack, G., Heutschi, D., Gaiser, C., Garcia, C., Carmo, S. D., Cuello, A. C., Morelli, L., & Suter-Dick, L. (2026). Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis. Neurobiology of Aging, 161, 47–63. https://doi.org/10.1016/j.neurobiolaging.2026.01.006

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