Abstract
Background and aims Chronically elevated levels of circulating lipoprotein-amyloid-β (Aβ) are implicated in the disruption of the blood-brain barrier and the initiation of a neurodegenerative cascade leading to Alzheimer’s disease (AD). Type 2 diabetes is associated with BBB dysfunction, dyslipidaemia, and an increased risk of AD. However, alterations in triglyceride-rich lipoproteins (TRL)-Aβ homeostasis and its downstream effects on the BBB in a diabetes context remain explored. This study aimed to 1) investigate, in a preclinical model of diabetes, the hypothesis that diabetes-induced impairments in TRL-Aβ metabolism might compromise BBB integrity and exacerbate cognitive function and behavioural changes, and 2) assess the efficacy of interventions that improve TRL catabolism, including probucol, HA1, and ApoC3 siRNA, to prevent disease progression by lowering circulating TRL-Aβ levels.
Methods Five-week-old db/db mice underwent a 9- or 23-weeks dietary interventions with probucol, a probucol prodrug HA1, or a standard diet with four-weekly injections of ApoC3 siRNA. Db/+ mice served as negative controls for each treatment duration. Blood levels of Aβ and ApoB were measured using ELISA. Immunofluorescence imaging was used to quantify enterocytic levels of Aβ and ApoB, and assess changes in neurovascular integrity (IgG, PDGFRβ, ZO1, occludin), neuroinflammation (GFAP, Iba1), and cerebral oxidative stress (8OHdG).
Results Our results indicate that diabetes increased the abundance of plasma amyloid, specifically Aβ42, which correlated with enterocytic abundance, suggesting exaggerated postprandial excretion. Disrupted plasma amyloid homeostasis was associated with BBB breakdown, including diminished barrier function, and the loss of pericytes and astrocytes. Provision of the probucol analogue, HA1, normalised plasma and enterocytic amyloidemia concomitant with the preservation of the neurovascular junction. Treatment with ApoC3 siRNA attenuated plasma Aβ42 and modestly reduced neurovascular inflammation.
Conclusion The findings further support the hypothesis that aberrant peripheral metabolism of lipoprotein-Aβ is associated with microvascular corruption and the development of anxiety-like behaviour. HA1 is more effective than probucol or ApoC3 siRNA in positively modulating lipoprotein-amyloid homeostasis in db/db mice and maintaining central capillary integrity.
Highlights
Enterocytic and plasma lipoprotein-Aβ levels are increased in diabetic db/db mice.
Elevated plasma lipoprotein-Aβ levels correlate with BBB breakdown and anxiety-like behavior.
HA1 lowers enterocytic and plasma Aβ levels, protects BBB, alleviates oxidative stress and anxiety.
ApoC3 siRNA lowers plasma lipoprotein-Aβ, mitigates neuroinflammation and anxiety.
Competing Interest Statement
The authors have declared no competing interest.
