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Updated: May 16, 2026
15:04
Interactions with and Membrane Permeabilization of Brain Mitochondria by Amyloid Fibrils
Published on: September 28, 2019
Insulin has multiple antiamyloidogenic effects on human neuronal cells
Giuseppe Pandini1, Vincenza Pace, Agata Copani
1Department of Clinical and Molecular Biomedicine, Endocrinology Unit, University of Catania, Garibaldi-Nesima Hospital, Via Palermo 636, Catania 95122, Italy.
Endocrinology
|December 15, 2012
Summary
Insulin influences brain amyloid precursor protein (APP) processing and beta-amyloid (Aβ) accumulation. This study reveals insulin
Area of Science:
- Neuroscience
- Molecular Biology
- Endocrinology
Background:
- Alzheimer's disease (AD) risk is elevated in diabetic patients.
- Brain insulin signaling defects are implicated in AD pathogenesis.
- The precise molecular mechanisms linking insulin to AD remain unclear.
Purpose of the Study:
- To investigate insulin's effects on amyloid precursor protein (APP) processing.
- To determine insulin's impact on beta-amyloid (Aβ) intracellular accumulation.
- To elucidate the molecular pathways involved in insulin's modulation of APP metabolism.
Main Methods:
- Utilized human neuronal cell lines and HEK293 cells overexpressing APP-695.
- Analyzed APP phosphorylation, subcellular localization, and gene transcription.
- Employed cell fractionation, immunofluorescence, and Gsk-3β inhibition/mutation studies.
Main Results:
- Insulin rapidly dephosphorylates APP at the T668 site via the PI3K/AKT pathway.
- Insulin prevents nuclear translocation of APP intracellular domain, upregulating anti-amyloidogenic genes (e.g., IDE, α-secretase) and downregulating pro-amyloidogenic genes (e.g., APP, β-secretase, Gsk-3β).
- Insulin promotes non-amyloidogenic APP processing, reducing intracellular Aβ40/Aβ42 accumulation and enhancing extracellular release through both Gsk-3β-dependent and independent mechanisms.
Conclusions:
- Insulin modulates APP processing and Aβ metabolism through multiple pathways.
- Insulin signaling in the brain may offer a therapeutic strategy for Alzheimer's disease.
- Understanding insulin's role in neuronal function is crucial for neurodegenerative disease research.
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