Elucidating the effects of a high fat diet on markers of brain insulin signaling, gliosis and synaptic integrity in mice with humanized APOEε3

• Background: Mid-life obesity is associated with an increased risk of dementia, including Alzheimer’s disease (AD). Elevated circulating free fatty acids were previously shown tohamper insulin transport across the blood-brain barrier (BBB) and dysfunctional brain insulin signaling in turn negatively affects cognition by modulating excitatory synapses. Addressing links between diet, lipid metabolism and cognition in vivo is complicated by species-specific differences in lipid metabolism. Here we used FRGN mice with humanized livers of the AD risk-neutral APOEε3/ε3 genotype to explore the effects of a high-fat diet (HFD) on markers of insulin signaling, gliosis and synaptic integrity in the brain.Methods: FRGN mice (n=11) with humanized livers of the APOEε3/ε3 genotype were fed normal chow (n=3) versus a HFD for 12 (n=5) or 20 weeks (n=3). Brain cortical and hippocampal tissues were biochemically analysed for changes in markers of gliosis, synaptic integrity, glucose transporters and insulin signaling. Immunohistochemistry (IHC) was used to assess whether the identified changes replicated at the histological level.Results: Humanization of the mouse liver produced human-like levels of plasma apolipoprotein B and low-density lipoprotein, which were further increased by a 12 week HFD. Mice on the HFD exhibited increased phosphorylation of the insulin receptor substrate 1 (IRS-1) at Ser-616, previously linked to brain insulin resistance, in parallel with reduced cortical marker levels of synaptic AMPAR. Markers of hippocampal insulin signaling were unaffected by the HFD however we observed an increase in the astrocytic marker GFAP but not the microglia- associated IBA1, and intracellular apolipoprotein E (apoE) levels alongside altered levels of the postsynaptic AMPA receptors and PSD-95. Hippocampal and cortical marker levels of the pre-synaptic synaptophysin were increased. The observed changes in the brain tissues were subtle and only alterations in the synaptophysin levels were corroborated using IHC.Conclusions: Our findings suggest that a HFD alters insulin signaling specifically in the cortex, and the levels of AMPAR, PSD-95, synaptophysin and apoE in the brains of FRGN mice with humanized livers, in the absence of microglia activation. These findings support a key role of the diet in brain health with implications for diseases like AD.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine (hsv//eng)

Nyckelord

Alzheimer’s disease

obesity

high-fat diet

lipid metabolism

insulin resistance

synapse integrity

neurokemi med molekylär neurobiologi

Neurochemistry with Molecular Neurobiology

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