MEET QPS AT AD/PD™ 2024; March 5-9, Lisbon, Portugal

Activating Low Density Lipoprotein Receptor Related Protein 1 (LRP1) To Improve Aβ Clearance Through The Blood Brain Barrier

QPS Neuropharmacology

In his PhD project, Joshua Adekunle Babalola from the Medical University of Graz investigates the effect of astaxanthin on Aβ clearance and the functional consequences thereof. Transport across the blood-brain barrier (BBB) is an important mediator of beta-amyloid (Aβ) accumulation in the brain and a contributing factor in the pathogenesis of Alzheimer’s disease (AD). One of the receptors responsible for the transport of Aβ through the BBB is the low-density lipoprotein receptor-related protein 1 (LRP1). LRP1 is an endocytic receptor or co-receptor of many ligands and at the transcriptional level, the LRP1 gene is regulated by PPARγ, indicated by the presence of the peroxisome proliferator response element (PPRE) in the LRP1 promoter region. LRP1 expression at the BBB is reduced during aging and in AD. Astaxanthin, a lipid-soluble xanthophyll β-carotenoid is a known PPAR-α agonist and PPAR-γ antagonist with anti-oxidative, anti-inflammatory and neuroprotective functions. Hence, Joshua evaluates if LRP1 activity in Brain Capillary Endothelial Cells (BCEC) can be modulated using astaxanthin to improve Aβ clearance and ameliorate other systemic dysfunctions at the BBB.

Porcine BCECs showed enhanced expression of LRP1 when treated with astaxanthin (Fig. 1A & 1B). Increased expression of autophagy (Fig. 2A) and insulin signalling markers (data not shown) were observed when pBCECs pre-incubated with astaxanthin were further treated with Aβ peptides. Astaxanthin activates GSK3β phosphorylation (Fig. 2B) and inhibits mTORC1 signaling (Fig. 2C) in Aβ peptide-treated pBCECs.

So far, Joshua has revealed that astaxanthin enhances LRP1 expression, insulin sensitivity and autophagy induction. Next, Joshua will evaluate the effect of astaxanthin on the behavior and neuropathology of an AD mouse model.

Figure 1

Figure 1: Astaxanthin (ASX) increases the expression level of LRP1 compared to vehicle control (VEH) at both mRNA (A) and protein level (B) in pBCEC. n = 3-6; mean + SEM; one-way ANOVA followed by Dunnett’s post hoc test compared to vehicle; *p < 0.05; **p < 0.01; n.s.: not significant.     Figure 2

Figure 2: Astaxanthin induces autophagy and GSK3β phosphorylation and inhibits mtorc1 pathway in Aβ-treated pBCEC. Densitometric evaluation of LC3B-II (A), p-GSK3β (B) and p-mTOR/mTOR (C) in Aβ-treated pBCEC, n=2; mean + SEM; one-way ANOVA followed by Dunnett’s post hoc test; *p < 0.05; n.s.: not significant.

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