Journal Article

DZNE-2026-00492

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png High-Fat Diet and a High Amyloid Load Interact to Induce PKC-α Dependent Synaptic Insulin Resistance.

Wenger, A. ; Li, T. ; Nguyen, C. ; Celik, A. ; Cuboni, E. ; Dityatev, A.DZNE* ; Karpova, A. ; Kreutz, M. R.DZNE* ; Ahrends, R.

2026
The American Society for Biochemistry and Molecular Biology Bethesda, Md.

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Please use a persistent id in citations: doi:10.1016/j.mcpro.2026.101537

Abstract: A plethora of studies suggest that a high-fat diet in combination with a high amyloid load causes synaptic insulin resistance and is a risk factor for Alzheimer's disease. Our understanding of the underlying mechanisms is still fragmented. To gain new insights, we conducted integrated proteomic and phosphoproteomic profiling of hippocampal synaptosomes from WT and a transgenic mouse line with a high amyloid load (heterozygous TBA2.1 mice) that show no overt signs of neurodegeneration and dementia. Mice were fed with a regular or high-fat diet. Data-independent acquisition quantified over 5400 proteins, revealing a stable synaptic proteome across conditions. However, the combination of high amyloid load and high-fat diet triggered coordinated remodeling of lipid metabolism pathways, particularly mitochondrial and peroxisomal fatty acid catabolism. Phosphoproteomic analysis showed pronounced activation of lipid- and stress-responsive kinases, including protein kinase C-α, along with increased inhibitory phosphorylation of insulin receptor substrates (IRS1/2). In vitro experiments indicate that blocking protein kinase C-α indeed prevents synaptic insulin resistance in primary neurons. The findings suggest that this proteomic workflow, combined with kinase pathway analysis, can reveal nodal points for interventions in a complex disease state with a trajectory to Alzheimer's disease.

Keyword(s): Animals (MeSH) ; Insulin Resistance (MeSH) ; Diet, High-Fat: adverse effects (MeSH) ; Mice, Transgenic (MeSH) ; Mice (MeSH) ; Protein Kinase C-alpha: metabolism (MeSH) ; Synapses: metabolism (MeSH) ; Hippocampus: metabolism (MeSH) ; Synaptosomes: metabolism (MeSH) ; Proteomics: methods (MeSH) ; Lipid Metabolism (MeSH) ; Phosphorylation (MeSH) ; Neurons: metabolism (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Male (MeSH) ; Amyloid: metabolism (MeSH) ; Mice, Inbred C57BL (MeSH) ; Alzheimer’s disease ; TMT ; enrichment analysis ; high-fat diet ; network analysis ; phosphoproteomics ; synaptic insulin resistance ; synaptosomes ; Protein Kinase C-alpha ; Amyloid

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Contributing Institute(s):

1. Molecular Neuroplasticity (AG Dityatev)
2. Clinical Neurophysiology and Memory (AG Düzel)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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