Dataset Information

High-fat diet and a high amyloid load interact to induce PKC-α dependent synaptic insulin resistance

ABSTRACT: Synaptic insulin resistance has been proposed as a mechanistic link between high-fat diet exposure, elevated amyloid burden, and vulnerability to Alzheimer’s disease. To investigate molecular changes associated with this state at the synapse, we performed integrated global proteomic and phosphoproteomic profiling of hippocampal synaptosomes isolated from wild-type mice and heterozygous TBA2.1 mice (high amyloid load without overt neurodegeneration) maintained either on a regular or high-fat diet. Proteins and phosphosites were quantified by data-independent acquisition (DIA), identifying >5,400 proteins across experimental conditions. While the baseline synaptic proteome remained largely stable, the combination of amyloid load and high-fat diet was associated with coordinated remodeling of lipid metabolism pathways, with signatures pointing to mitochondrial and peroxisomal fatty acid catabolism. Phosphoproteomics revealed activation of lipid- and stress-responsive kinase pathways, including PKC-α, and increased inhibitory phosphorylation of IRS1/2. Complementary in vitro assays confirmed that pharmacological inhibition of PKC-α prevented the emergence of synaptic insulin resistance in primary neurons. These datasets provide a resource for studying diet- and amyloid-dependent signaling alterations at the synapse in the context of Alzheimer’s-relevant disease drivers.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Alexander Wenger

LAB HEAD: Robert Ahrends

PROVIDER: PXD069785 | Pride | 2026-04-13

REPOSITORIES: Pride

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Publications

High-Fat Diet and a High Amyloid Load Interact to Induce PKC-α Dependent Synaptic Insulin Resistance.

Wenger Alexander A Li Tingting T Nguyen Chi C Celik Ali A Cuboni Eleonora E Dityatev Alexander A Karpova Anna A Kreutz Michael R MR Ahrends Robert R

Molecular & cellular proteomics : MCP 20260223 4

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 dementi ...[more]

PMID: 41740736

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