Microglia-Mediated Neurovascular Unit Dysfunction in Alzheimer's Disease

Abstract

The neurovascular unit (NVU) is involved in the pathological changes in Alzheimer's disease (AD). The NVU is a structural and functional complex that maintains microenvironmental homeostasis and metabolic balance in the central nervous system. As one of the most important components of the NVU, microglia not only induce blood-brain barrier breakdown by promoting neuroinflammation, the infiltration of peripheral white blood cells and oxidative stress but also mediate neurovascular uncoupling by inducing mitochondrial dysfunction in neurons, abnormal contraction of cerebral vessels, and pericyte loss in AD. In addition, microglia-mediated dysfunction of cellular components in the NVU, such as astrocytes and pericytes, can destroy the integrity of the NVU and lead to NVU impairment. Therefore, we review the mechanisms of microglia-mediated NVU dysfunction in AD. Furthermore, existing therapeutic advancements aimed at restoring the function of microglia and the NVU in AD are discussed. Finally, we predict the role of pericytes in microglia-mediated NVU dysfunction in AD is the hotspot in the future.

Keywords: Alzheimer’s disease; blood-brain barrier; microglia; neurovascular uncoupling; neurovascular unit; pericyte.

Fig. 1

Microglia mediate BBB dysfunction. Firstly, microglia induced by Aβ secrete IL-1β, TNF-α, MMP-9, and CCL2 to destroy TJs and AJs between BMECs and increase the expression of leukocyte adhesion molecules (LAMs) on BMECs to attract peripheral WBCs. Secondly, activated microglia secrete C1q, TNF-α and IL-1β to activate astrocytes. The activated astrocytes promote transmigration of peripheral WBCs across BBB by secreting CCL2 and induce BBB breakdown by secreting C3 and vascular endothelial growth factors (VEGF). Thirdly, activated microglia mediate pericyte dysfunction by secreting TNF-α and presenting Aβ to Th1 cells. Then, activated pericytes increase the release of MMP-9 to destroy TJs leading to BBB impairment.

Fig. 2

Microglia mediate neurovascular uncoupling. Firstly, microglia induced by Aβ secrete ROS and IL-1β to induce neuronal mitochondrial dysfunction directly. Then, activated microglia also secrete C1q, TNF-α, TGF-β to activate astrocytes. And activated astrocytes increase the release of glutamate and C3 to induce neuronal mitochondrial dysfunction. As a result, neuronal mitochondrial dysfunction induces degeneration of more surrounding neurons by releasing ROS and EVs, finally leading to neurovascular uncoupling. Meanwhile, microglia are involved in the regulation of neurovascular uncoupling by affecting the function of cerebral vessels. Aβ induces abnormal contraction of small arteries by promoting the conversion of VSMCs to hypercontractive phenotype. And Aβ also induces abnormal contraction of capillaries by increasing the release of ROS of pericytes. Eventually, microglia aggravate the effects of Aβ by secreting IL-1β to increase the release of Aβ of neurons.

Fig. 3

Microglia mediate astrocyte dysfunction. Firstly, activated microglia secrete TNF-α, C1q, and NO to activate astrocytes. And activated astrocytes increase the release of C3 to mediate NVU dysfunction by regulating the function of BMEC, microglia, and neuron. Secondly, microglia secrete TNF-α and IL-1β to increase the expression of BACE-1 in astrocyte to aggravate Aβ accumulation and destroy GJs between astrocytes to affect normal cellular communication between astrocytes. And TNF-α also increases the expression of PG in astrocyte to evoke calcium ion-mediated release of glutamate which induces the apoptosis of neuron. Thirdly, microglia-derived TGF-β increases the expression of KCa3.1 channel which works together with elevated calcium ion in astrocytes to promote release of glutamate.