Work

Galectin‐1 targets brain endothelial cell changes, reduces vascular amyloid deposition and restores blood‐brain barrier (BBB) integrity in Alzheimer's Disease models

Year: 2025

Type: article

Abstract: BACKGROUND: Alzheimer's disease (AD) is characterized by neuroinflammation, vascular dysfunction, and impaired proteostasis. Galectin-1 (Gal1), a carbohydrate-binding protein with immunomodulatory and vascular regulatory roles, emerges as a potential therapy for AD. METHODS: We integrated in vitro and in vivo AD experimental models to evaluate the role of Gal1 in AD pathophysiology using human brain microvascular endothelial cells (HBMECs) exposed to Aβ1-40 and PDAPPJ20 transgenic (Tg) mice treated with Gal1 (9 doses of 100 µg). We evaluated the impact of Gal1 administration on AD-related changes using multiple approaches including immunofluorescence, confocal microscopy, flow cytometry, transwell, RT-PCR, BBB permeability assays, and RNAseq. Custom macros in FIJI were used for image analysis. Parametric and non-parametric statistical analyses, where appropriate, were performed using R/Graphpad software. RESULTS: In vitro, Aβ1-40-exposed HBMECs upregulated endogenous Gal1 protein at subtoxic concentrations, suggesting a compensatory protective mechanism (p <0.05). Gal1 directly bound HBMECs via its carbohydrate recognition domain and prevented Aβ-induced BBB disruption in a transwell model (p <0.05). In addition, Gal1 restored Aβ 1-42 uptake by HBMECs (p <0.05), probably through improved proteostasis and consequently intracellular trafficking. Accordingly, Gal1 counteracted Aβ-induced prolonged activation of the unfolded protein response effectors BIP(p <0.01), IRE1, PERK, and XBP1 (all p <0.05), as well as the NLRP3 inflammasome in HBMECs (p <0.05). In vivo, Gal-treated Tg mice showed a significant reduction in perivascular amyloid deposition in the hippocampus (p <0.05). Astrocyte-endothelial interactions, critical for blood-brain barrier (BBB) integrity, were restored as evidenced by increased astrocytic endfeet contact (GFAP-lectin staining) and perivascular aquaporin-4 colocalization (p <0.02). BBB permeability was reduced in Gal1-treated Tg mice (Evans blue assay, p <0.05). RNAseq analysis of whole hippocampal brain tissue from Tg mice revealed extensive alterations in key pathways related to immune function, neuronal activity and proteostasis networks, while Tg-Gal1 mice showed a restored transcriptional profile similar to control mice. Gal1-treated Tg mice showed reduced XBP1 vascular presence in the hippocampal hilus compared to untreated mice (p <0.05), further validating the in vitro results. CONCLUSIONS: These novel findings position Gal1 as a pleiotropic modulator of AD pathology, with a focus on microvascular changes. Given the multifactorial nature of this pathology, Gal1-based strategies could target disease mechanisms at multiple levels.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz70855_107216