Defects in insulin production and signaling are suspected to share a key role in diabetes and Alzheimer disease (AD), two age-related pathologies. In this study, we investigated the interrelation between AD and diabetes using a high-fat diet (HFD) in a mouse model of genetically induced AD-like neuropathology (3xTg-AD). We first observed that cerebral expression of human AD transgenes led to peripheral glucose intolerance, associated with pancreatic human Aβ accumulation. High-fat diet enhanced glucose intolerance, brain soluble Aβ, and memory impairment in 3xTg-AD mice. Strikingly, a single insulin injection reversed the deleterious effects of HFD on memory and soluble Aβ levels, partly through changes in Aβ production and/or clearance. Our results are consistent with the development of a vicious cycle between AD and diabetes, potentiating both peripheral metabolic disorders and AD neuropathology. The capacity of insulin to rapidly break the deleterious effects of this cycle on soluble Aβ concentrations and memory has important therapeutic implications.

Long‐term high‐fat diet–induced changes in liver function impact peripheral AD features and should be considered during development of biomarkers or therapeutic targets.

No model fully recapitulates the neuropathology of Alzheimer's disease (AD). Although the triple-transgenic mouse model of AD (3xTg-AD) expresses Aβ plaques and tau-laden neurofibrillary tangles, as well as synaptic and behavioral deficits, it does not display frank neuronal loss. Because old age is the most important risk factor in AD, senescence-related interactions might be lacking to truly establish an AD-like environment. To investigate this hypothesis, we bred the 3xTg-AD mouse with the senescence-accelerated mouse prone 8 (SAMP8), a model of accelerated aging. We generated four groups of heterozygous mice with either the SAMP8 or SAMR1 (senescence-resistant-1) genotype, along with either the 3xTg-AD or non-transgenic (NonTg) genotype. Despite no differences among groups in total latency to escape the Barnes maze, a greater number of errors were noticed before entering the target hole in 19-month-old P8/3xTg-AD mice at day 5, compared to other groups. Postmortem analyses revealed increased cortical levels of phospho-tau (Thr231) in female P8/3xTg-AD mice (+277% vs. R1/3xTg-AD mice), without other tau-related changes. Female P8/3xTg-AD mice exhibited higher cortical soluble Aβ40 and Aβ42 concentrations (Aβ40, +85%; Aβ42, +35% vs. R1/3xTg-AD), whereas insoluble forms remained unchanged. Higher Aβ42 load coincided with increased astroglial activation in female P8/3xTg-AD mice, as measured with glial fibrillary acidic protein (GFAP) (+57% vs. R1/3xTg-AD mice). To probe neuronal degeneration, concentrations of neuronal nuclei (NeuN) were measured, but no differences were detected between groups. Altogether, the SAMP8 genotype had deleterious effects on spatial memory and exerted female-specific aggravation of AD neuropathology without overt neurodegeneration in 3xTg-AD mice.

Arachidonic acid can be metabolized by cytochrome P450 (CYP450) enzymes in a tissue- and cell-specific manner to generate vasoactive products such as epoxyeicosatrienoic acids (EETs-cardioprotective) and hydroxyeicosatetraenoic acids (HETEs-cardiotoxic). Type II diabetes is a well-recognized risk factor for developing cardiovascular disease. A mouse model of Type II diabetes (C57BLKS/J-db/db) was used. After sacrifice, livers and hearts were collected, washed, and snap frozen. Total proteins were extracted. Western blots were performed to assess cardiac CYP2J and hepatic CYP2C, CYP4A, and CYP4F protein expression, respectively. Significant decreases in relative protein expression of cardiac CYP2J and hepatic CYP2C were observed in Type II diabetes animals compared to controls (CYP2J: 0.80 ± 0.03 vs. 1.05 ± 0.06, n = 20, p < 0.001); (CYP2C: 1.56 ± 0.17 vs. 2.21 ± 0.19, n = 19, p < 0.01). In contrast, significant increases in relative protein expression of both hepatic CYP4A and CYP4F were noted in Type II diabetes mice compared to controls (CYP4A: 1.06 ± 0.09 vs. 0.18 ± 0.01, n = 19, p < 0.001); (CYP4F: 2.53 ± 0.22 vs. 1.10 ± 0.07, n = 19, p < 0.001). These alterations induced by Type II diabetes in the endogenous pathway (CYP450) of arachidonic acid metabolism may increase the risk for cardiovascular disease by disrupting the fine equilibrium between cardioprotective (CYP2J/CYP2C-generated) and cardiotoxic (CYP4A/CYP4F-generated) metabolites of arachidonic acid.

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Background Defects in central response to insulin is suspected to play a role in AD. However, to act on the brain, pancreas‐secreted insulin must interact first with the blood‐brain barrier (BBB). The aim of the present study was to better understand mechanisms underlying transport and cell‐signaling of insulin at the BBB, and how they are altered in AD. Method We used microvessel‐enriched brain samples from individual classified as Controls, MCI or AD and from 3xTg‐AD mice from different ages, exposed or not to a high fat diet. In situ cerebral perfusion was used to quantify the transport of [125I] insulin across the BBB. Results We first show that insulin receptors (INSR) in human and mouse brains are concentrated in blood microvessels. We observed lower concentrations of INSRα in microvessel extracts from the parietal cortex of AD patients, associated with cognitive symptoms. We also observed a shift toward a higher INSRα‐A: INSRα‐B ratio in AD, which is consistent with insulin resistance. We next looked at insulin‐activated cell‐signaling pathways within microvessels and found that activation was reduced in 3xTg‐AD mice, following a high‐fat diet. Although it is assumed that insulin crosses the BBB, we found that its transport rate remained very low and was not antagonized by INSR blockers. Finally, we provide some insights on the regulation of brain beta‐amyloid levels following the activation of BBB INSR. Conclusion Overall, our data support the hypothesis of brain insulin resistance in AD, but at the level of INSR localized in microvessels. This also suggests that the INSR and its downstream signaling within endothelial cells of the BBB may be a systemically accessible drug target in AD.