Effects of HA1, a probucol analogue, and APOC3 siRNA on lipoprotein and amyloid-β metabolism and neurovascular dysfunction in type 2 diabetic mice.

INTRODUCTION: Chronic vascular exposure to elevated levels of lipoprotein-amyloid-β (Aβ) contributes to blood-brain barrier (BBB) disruption and the pathogenesis of Alzheimer's disease (AD). Therapeutic agents such as probucol have been shown to reduce circulating lipoprotein-Aβ levels and mitigate neurovascular dysfunction and cognitive decline. Type 2 diabetes (T2D) impairs BBB integrity and is characterised by dyslipidaemia and metabolic disturbances that may influence the peripheral metabolism of lipoprotein-Aβ. However, the effects of diabetes on lipoprotein-Aβ homeostasis and neurovascular integrity remain poorly understood. This study investigated whether diabetes impairs lipoprotein and Aβ metabolism and whether treatment with HA1, a probucol analogue with improved bioavailability, or APOC3 siRNA can modify these metabolic changes and improve neurovascular and behavioural outcomes. METHODS: Non-diabetic db/+ mice, untreated diabetic db/db mice, and diabetic db/db mice treated with HA1 or APOC3 siRNA were used to determine how diabetes and therapeutic modulation of lipoprotein metabolism affect circulating Aβ, neurovascular integrity, and behavioural outcomes. Total plasma Aβ and ApoB levels were measured by ELISA. Intestinal Aβ and ApoB, neurovascular integrity, neuroinflammation, and oxidative stress were assessed by immunofluorescence. Anxiety-like behaviour and short- and long-term memory were evaluated using the open field, novel object recognition, and passive avoidance tests. RESULTS: Diabetic db/db mice exhibited increased intestinal Aβ and ApoB immunoreactivity and elevated total plasma Aβ42, Aβ oligomer and ApoB, accompanied by heightened BBB permeability and anxiety-like phenotype. HA1 reduced intestinal Aβ and lowered plasma Aβ42 and Aβ oligomer, prevented IgG extravasation, and improved anxiety. APOC3 siRNA lowered plasma ApoB and plasma Aβ42 and attenuated neuroinflammation, but did not reduce IgG extravasation. CONCLUSION: Dysregulated lipoprotein and Aβ metabolism are associated with neurovascular dysfunction and anxiety-like behaviour in diabetes. HA1 shows therapeutic potential by modulating Aβ metabolism and improving neurovascular and behavioural outcomes.