This study used mouse models fed a high-fat diet (HFD) to induce features of metabolic syndrome including peripheral insulin resistance and obesity, and compared them with mice fed a low-fat diet (LFD). The authors hypothesized that insulin resistance alters blood-brain barrier (BBB) transport of amyloid-beta (Aβ) peptides and glucose, thereby contributing to pathological changes associated with Alzheimer’s disease (AD).
To test the hypothesis, the investigators employed radiolabeled ligands to quantify BBB transport in vivo. They used 125I-labeled Aβ peptides (125I-Aβ40 and 125I-Aβ42) to assess Aβ influx and 18F-FDG as a surrogate tracer for glucose transport into the brain. Compared with LFD-fed controls, HFD-fed mice demonstrated an increased influx rate of Aβ peptides from plasma-to-brain and a reduced influx rate of 18F-FDG. These opposing changes indicate a shift at the BBB toward greater Aβ delivery to the brain while diminishing glucose availability.
Investigators harvested brain microcapillaries to examine molecular mediators of transport at the endothelial layer of the BBB. In HFD-fed mice, endothelial expression of RAGE—the receptor implicated in trafficking Aβ from plasma to brain—was elevated. In contrast, expression of GLUT1, the principal endothelial glucose transporter at the BBB, was reduced in HFD-fed mice relative to LFD-fed mice. The observed transport phenotypes (increased Aβ influx and decreased glucose uptake) were associated with these expression changes, supporting a mechanistic link between diet-induced metabolic alterations and modified BBB transporter/receptor profiles.
The study reports disruption of insulin signaling within brain microvasculature from HFD-fed mice. Specifically, phosphorylation of canonical signaling mediators AKT (pAKT) and ERK (pERK) was reduced in HFD-fed animals, indicating impaired insulin-responsive pathways in the BBB endothelium. These signaling deficits were presented as correlates of the transporter and receptor expression changes described above.
To probe causality between insulin signaling and transport changes, the authors used polarized BBB endothelial cell monolayers in vitro. Pharmacologic inhibition of AKT or ERK phosphorylation in these cell models produced patterns of altered uptake that mirrored the in vivo observations—namely, increased Aβ uptake and decreased glucose uptake. These in vitro results support the interpretation that impaired AKT/ERK signaling in BBB endothelial cells can drive reciprocal changes in Aβ and glucose transport.
The integrated in vivo and in vitro findings reported by the authors indicate that HFD-induced metabolic syndrome may produce a form of BBB dysfunction characterized by two concurrent transport disturbances: enhanced plasma-to-brain trafficking of amyloid-beta and reduced glucose transport across the BBB. Given that Aβ accumulation and cerebral hypometabolism are hallmark features of AD pathology, the authors suggest that diet- and insulin-resistance–associated BBB changes could aggravate or accelerate AD-related pathological processes by increasing Aβ delivery to the brain while limiting glucose availability.
The source reports competing interest disclosures: one author has listed consulting relationships and research support from multiple industry partners; another author is an employee of Johnson & Johnson Innovative Medicine Research & Development; the remaining authors declared no potential conflicts. Funding declared in the source includes Minnesota Partnership for Biotechnology and Medical Genomics and grants from National Institutes of Health institutes (including NINDS and NIA). The preprint status of the source indicates these results are new and were posted as a preprint; details such as sample sizes, statistical values, and additional methodological specifics were presented in the original manuscript but are not reproduced here.