Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance

Abstract

PICALM is highly validated genetic risk factor for Alzheimer’s disease (AD). Here, we report that PICALM reductions in AD and murine brain endothelium correlate with amyloid–β (Aβ) pathology and cognitive impairment. Moreover, Picalm deficiency diminishes Aβ clearance across the murine blood–brain barrier (BBB) and accelerates Aβ pathology that is reversible by endothelial PICALM re–expression. Using human brain endothelial monolayer, we show that PICALM regulates PICALM/clathrin–dependent internalization of Aβ bound to the low density lipoprotein receptor related protein–1, a key Aβ clearance receptor, and guides Aβ trafficking to Rab5 and Rab11 leading to Aβ endothelial transcytosis and clearance. PICALM levels and Aβ clearance were reduced in AD–derived endothelial monolayers, which was reversible by adenoviral–mediated PICALM transfer. iPSC–derived human endothelial cells carrying the rs3851179 protective allele exhibited higher PICALM levels and enhanced Aβ clearance. Thus, PICALM regulates Aβ BBB transcytosis and clearance that has implications for Aβ brain homeostasis and clearance therapy.

Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier

“…Differential binding affinity of LRP1 to Aβ (12,13). However, controversial findings from different groups and the lack of appropriate models to study BBB transporters have created growing ambiguity in the field (8,11,12,15,(17)(18)(19)47).…”

“…Moreover, LRP1 is further reduced in AD (8,10). Additionally, highly validated genetic risk factors for AD, like the apolipoprotein E (apoE) Ε4 allele or the gene encoding the phosphatidylinositol-binding clathrin assembly (PICALM), are believed to be linked to reduced clearance of Aβ via LRP1 (11)(12)(13). In senile plaques, LRP1 ligands, like apoE, urokinase-type plasminogen activator, tissue plasminogen activator, and lactoferrin, co-deposit with Aβ, all together indicating a loss of LRP1 function in AD (14).…”

Vascular and Metabolic Factors in Alzheimer’s Disease and Related Dementias: Introduction

“…Brain Aβ clearance is thought to rely on parenchymal and vascular mechanisms (Miners et al, 2014). In addition to parenchymal enzymes that degrade Aβ (neprilysin, insulin degrading enzyme, plasmin, and endothelin converting enzyme) (Miners et al, 2008), Aβ is removed (a) through perivascular pathways draining into the cervical lymphnodes (Tarasoff-Conway et al, 2015), and (b) by binding vascular transport receptors (LRP1, PICALM) and crossing the vascular wall to reach the circulation (Shibata et al, 2000; Storck et al, 2015; Zhao et al, 2015). A paravascular pathway involving astrocytic end-feet (glymphatic system), which has the potential to clear Aβ from the brain (Iliff et al, 2012), has been recently discovered and could play a role.…”

Complexity across scales: a walkthrough to linking neuro-imaging readouts to molecular processes

“…As PICALM plays a major role in the internalization of the endothelial proteins, it also internalizes the sLRP1 and amyloidbeta complex by trafficking through two other proteins Rab5 and Rab11. These further results in amyloid transcytosis and clearance from entering the BBB [180][181][182]. Also, LRP1 activates another protein called GLUT1 which is another major glucose transporter across the BBB [183][184][185].…”