ClearPath · Amyloid-β clearance in Alzheimer's disease: Unravelling the role of endocytic pathways of endothelial cells

Amyloid-β clearance in Alzheimer's disease: Unravelling the role of endocytic pathways of endothelial cells

Alzheimer’s disease (AD) is characterized by the progressive extracellular accumulation of β-amyloid peptide (Aβ) in the brain, leading to the formation of amyloid plaques. Aβ deposition is a major risk factor for the onset and progression of AD. While research has traditionally focused on neurons, glial cells, and astrocytes, increasing evidence suggests that the brain’s vascular component plays a significant role in disease development. Notably, up to 80% of AD patients exhibit cerebral amyloid angiopathy (CAA), with Aβ accumulation in cerebral vessel walls, which disrupts vessel integrity and impairs blood-brain barrier (BBB) functionality. The brain vascular network also plays a critical role in Aβ clearance, maintaining low levels of this toxic peptide in the brain. Endothelial cells (ECs), which form the BBB, are central to this process. Clathrin-mediated endocytosis (CME) allows ECs to internalize Aβ from the neuronal side, transport it across the cell, and release it into the blood, facilitating delivery to peripheral tissues (e.g., liver) for degradation. Impaired CME in some AD patients contributes to Aβ accumulation in the brain. Importantly, CME is only one of several endocytic pathways utilized by ECs, and the contribution of other endocytic mechanisms to Aβ clearance remains largely unexplored. Overall Objectives Investigate the unexplored endocytic pathways involved in brain Aβ clearance. Identify the relationship between endocytic abnormalities and AD pathology. Approach To achieve these objectives, the project will: a. Develop and characterize a novel in vitro transwell BBB model using isogenic iPSC lines derived from AD patients with APOE 4/4 genotype. b. Utilize this model to identify distinct endocytic pathways involved in Aβ clearance. c. Perform large-scale bioinformatics analyses of genome-wide and transcriptome datasets from AD patients to identify novel disease-associated genes and pathways implicated in endocytic routes. This will enable the development of a genetic risk score for AD onset and MCI-to-AD progression. d. Validate in vitro findings in established AD animal models. Using the in vitro BBB model, we will examine the effects of Aβ peptides released from iPSC-derived neurons on the endothelial monolayer, focusing on the role of distinct endocytic pathways in Aβ clearance. A multidisciplinary approach, combining advanced cellular models, bioinformatics, and in vivo validation, will provide a comprehensive understanding of the endothelial component of the neurovascular unit. Expected Impact Understanding the mechanisms regulating Aβ clearance will provide critical insights into AD pathogenesis and may inform rational drug design. Given the growing prevalence of AD and the associated socioeconomic burden, identifying novel targets for intervention could accelerate the development of precision therapies. While the therapeutic potential of endocytic Aβ clearance is not yet established, this research will provide foundational knowledge for novel treatment strategies for AD and related neurodegenerative diseases.

Data: CORDIS, © European Union