Table 2.
Molecular Pathology of the Microcirculation and BBB in Late-Onset AD
| Cellular feature | Morphological changes | Biochemical markers |
|---|---|---|
| Cerebral endothelium loss of glucose transporter, Na+/K+ ATPase | Loss of cytoplasm and endoplasmic reticulum. Increased pinocytosis. | ↓ GLUT1, Na+/K+ ATPase, CD31, CD34 |
| Changes in cytoplasm (oxidative and endoplasmic reticulum stresses) | ↑ Glucose-6-phosphatase; proteases (endothelin converting enzyme-1) | |
| Endothelial membranes/microvascular endfeet | ↓ Alkaline phosphatase, γ-GGT, cholinesterases | |
| Decreased mitochondria | ↓ Carnitine acetyltransferase | |
| Loss of tight junctions | ||
| Vascular basement membrane | Thickening of the ECM, collagen fibers | ↑ COL, perlecans, fibrinogen, matrix metalloproteinases |
| Perivascular cells | Increased astrocytic feet | ↑ GFAP reactivity |
| Pericytes: cell numbers and coverage | ↑ CSF sPDGFRβ1; ↑ cortex PDGFRβ1cortex; ↓WM PDGFRβ1; ↑ perivascular macrophage markers, CD68, TREM2 | |
| Arteries/arterioles | Loss of vascular smooth muscle cells; increased microthrombi | ↓ α-Smooth muscle actin; accumulation of Aβ |
| Cerebral microvessels | Changes in endothelium and perivascular macrophages | ↑ Inflammatory mediators ICAM1 and cytokines |
Summary of observations derived from several previous studies.9,28,35 Arrows indicate decreases (↓) or increases (↑).
Aβ, amyloid β protein; AD, Alzheimer disease; AlkP, alkaline phosphatase; BBB, blood-brain barrier; CD, clusters of differentiation markers; CD31, CD34 cluster of differentiation markers 31 and 34 for endothelium; CD68, cluster of differentiation marker 68 for microglia; COL, collagens; CSF, cerebrospinal fluid; EC, endothelial cell; ECM, extracellular matrix; eNOS, endothelial nitric oxide synthase; GFAP, glial fibrillary acid protein; GGT, γ-glutamyl transpeptidase; GLUT1, glucose transporter 1; HIF-1α, hypoxia inducible factor 1α; NV, neurovascular; PDGFRβ, platelet-derived growth factor receptor β; PVS, perivascular space; SMC, smooth muscle cell; TREM2, triggering receptor expressed on myeloid cells 2; VEGF, vascular endothelial growth factor; WM, white matter.