Table 2.
Molecule factors of the BBB in aging, Alzheimer’s disease (AD), and vascular dementia (VaD). (BBB: blood–brain barrier, AD: Alzheimer’s disease, VaD: vascular dementia, CLDN5: claudin-5, OCLN: occludin, TJ protein: tight junction protein, EC: entorhinal cortex, Aβ: amyloid beta, ICAM-1: intercellular adhesion molecule 1, VCAM-1: vascular adhesion molecule 1, CCH: chronic cerebral hypoperfusion, SVD: small-vessel disease, PVMs: perivascular macrophages, ROS: reactive oxygen species, FB: fibroblast, GLUT1: glucose transporter, LRP1: low-density-lipoprotein (LDL)-receptor-related protein 1, Pgp: phosphoglycolate phosphatase, RAGE: advanced glycosylation end product (AGE) receptor, AQP4: aquaporin-4, APOE: apolipoprotein E, VLDLR: very-low-density lipoprotein receptor, CypA-NF-kb-MMP-9: cyclophilin-A nuclear factor κb-matrix metalloproteinase 9, MMP: matrix metalloproteinase, TGFβ: transforming growth factor beta, PDGFRb: pericytes express platelet-derived growth factor receptor beta, CSF: cerebrospinal fluid, sPDGFR: soluble PDGFR, CAMs: cell adhesion molecules, s4-1BBL: soluble 4-1BB ligand, PECAM-1: platelet endothelial cell adhesion molecule 1, VEGFA: vascular endothelial growth factor A, SPARC: secreted protein acidic and rich in cysteine, N/A: not applicable.
| Factors | Disease | Expressions or Levels | Phenotype | Reference |
|---|---|---|---|---|
| Glucose transporter (GLUT1) | AD | Decrease | Decreased in glucose concentrations in the CNS | [139] |
| LRP1 | AD | Decrease | Decreased with increasing oxidative stress | [130] |
| AD | Decrease | Decreased with increasing oxidative stress | [131] | |
| LRP1 and Pgp | AD mice | Decrease | Hinders amyloid clearance from the brain | [132] |
| RAGE | AD | Increase | Elevated in brain endothelial cells, promoting neuronal inflammation | [136] |
| Aquaporin-4 (AQP4) | AD | Decrease | Increasing neurofibrillary tangles | [109] |
| AD | Decrease | Increased amyloid-b eta pathology | [109] | |
| Apolipoprotein E 2/3 (ApoE 2/3) | Maintain BBB integrity | Increase | Interacts with LRP-1 in pericytes to block the “CypA-NF-kb-MMP-9” pathway, leading to the inhibition of MMPs | [111] |
| APOE4 | AD | Increase | Shifting the rapid clearance of soluble Ab40/42 by LRP1 to the slower clearance by VLDLR | [167] |
| AD | Increase | Reduced BBB integrity by promoting pericyte degeneration | [111] | |
| Endothelial LRP1 knockout mice | N/A | CypA-NFkB-MMP-9 activation | [173] | |
| Endothelial LRP1 knockout mice | N/A | TJ and BBB damage | [173] | |
| APOE4-transfected mice | Increase | Inhibits the expression of Glut1 | [37] | |
| APOE4-transfected mice | Increase | Increase expression of RAGE | [37] | |
| AD patients | Increase | More prone to BBB damage | [168] | |
| AD patients | Increase | Reduced pericytes | [130] | |
| TGFβ | AD transgenic mice | Increase | Abundantly expressed in astrocytes | [175] |
| AD transgenic mice | Increase | Promote amyloidosis | [175] | |
| AD transgenic mice | Increase | Promote amyloid clearance by microglia | [176] | |
| Platelet-derived growth factor receptor beta (PDGFRb) | Aging | Increase | Elevated in cerebrospinal fluid (CSF) | [178] |
| BBB damage | Increase | Impairment of pericytes | [178] | |
| Soluble PDGFR (sPDGFR) | Increase | Pericyte and blood–brain barrier disruption | [181] | |
| Pdgfr +/− pericyte-deficient mice | Increase | BBB impairment caused by neuronal degeneration | [48] | |
| AD patients | Increase | Leakage of the BBB in the hippocampus | [15] | |
| AD patients | Increase | Increased soluble PDGFRb (sPDGFRb) in cerebrospinal fluid | [182] | |
| Neurodegenerative diseases | Increase | As a biomarker in cerebrospinal fluid | [179] | |
| s100b | Stressed BBB | Increase | Protein biomarker produced by astrocyte endfeet | [190] |
| CAMs, zonulin, and s4-1BBL | BBB impairment | N/A | As biomarkers | [189] |
| PECAM-1, P-selectin, and E-selectin | BBB impairment | Increase | As biomarkers | [189] |
| RepSox | Neurological diseases | N/A | Inhibits TGF-B, VEGFA, and inflammation-related pathways | [191] |
| Neurological diseases | N/A | Increases BBB resistance and induces TJs and transporters | [191] | |
| Neurological diseases | N/A | Reduces paracellular permeability by activating Notch and Wnt pathways | [191] | |
| SPARC | AD | N/A | Reduces transendothelial electrical resistance (TEER) and TJs | [188] |
| AD | N/A | The SPARC–collagen binding domain can be a therapeutic target in AD | [188] | |
| AD | N/A | SPARC/Hevin can be a therapeutic target for modulating AD progression | [187] |