Drugs Modulating CD4+ T Cells Blood-Brain Barrier Interaction in Alzheimer's Disease

Abstract

The effect of Alzheimer's disease (AD) medications on CD4+ T cells homing has not been thoroughly investigated. CD4+ T cells could both exacerbate and reduce AD symptoms based on their infiltrating subpopulations. Proinflammatory subpopulations such as Th1 and Th17 constitute a major source of proinflammatory cytokines that reduce endothelial integrity and stimulate astrocytes, resulting in the production of amyloid β. Anti-inflammatory subpopulations such as Th2 and Tregs reduce inflammation and regulate the function of Th1 and Th17. Recently, pathogenic Th17 has been shown to have a superior infiltrating capacity compared to other major CD4+ T cell subpopulations. Alzheimer's drugs such as donepezil (Aricept), rivastigmine (Exelon), galantamine (Razadyne), and memantine (Namenda) are known to play an important part in regulating the mechanisms of the neurotransmitters. However, little is known about the effect of these drugs on CD4+ T cell subpopulations' infiltration of the brain during AD. In this review, we focus on understanding the influence of AD drugs on CD4+ T cell subpopulation interactions with the BBB in AD. While current AD therapies improve endothelial integrity and reduce astrocytes activations, they vary according to their influence on various CD4+ T cell subpopulations. Donepezil reduces the numbers of Th1 but not Th2, Rivastigmine inhibits Th1 and Th17 but not Th2, and memantine reduces Th1 but not Treg. However, none of the current AD drugs is specifically designed to target the dysregulated balance in the Th17/Treg axis. Future drug design approaches should specifically consider inhibiting CD4+ Th17 to improve AD prognosis.

Keywords: Alzheimer; CD4+ T cells; Th17; blood brain barrier; migration.

Figure 1

Naïve CD4+ T cells differentiation. After migrating from the thymus to the periphery, CD4+ T cells differentiate in the periphery into Th1, Th2, Th17, and Treg. CD4+ T cells are highly plastic with possibility of changing the fate of the cell based on its cytokines’ microenvironment. Tregs known for their ability to suppress proinflammatory CD4+ T cells can themselves be converted to highly pathogenic population under the action of IL-1, IL-6, and IL-23. Adapted from [4], copyright Bhaumik and Basu, 2017.

Figure 2

NVU is subjected to a vicious cycle of destruction in AD. (a) The main building blocks of the NVU unit includes endothelial cells, astrocytes, and pericytes. (b) Amyloid B deposition causes the BBB to lose its integrity, which in turn promotes infiltration of proinflammatory CD4+ T cells. Migrating CD4+ T cells produce proinflammatory cytokines that further increase the depiction of amyloid B.

Figure 3

A comparison between CD4+ T cells interaction with the BBB in health and disease. During homeostasis, ICAM1 and VCAM1 are downregulated to deter adhesion. Occludin, ZO1, ZO2, and ZO3 are upregulated to main integrity. Cadherin is upregulated and PECAM1 is downregulated to prevent infiltration. This picture is mirrored in case of pathology, where the BBB loses its integrity, becomes more permeable, and increases the possibility of lymphocytes adhesion through upregulating VAM1 and ICAM1. During homeostasis, astrocytes upregulate Cx43 and FASL to inhibit CD4+ T cells infiltration. During the earlier stages of the disease, they downregulate Cx43 and present amyloid to Th2. However, during late phases of the disease, astrocytes themselves become a source of amyloid βand produce IL-6 and IL-1B which help recruit more pathogenic Th17 that produce proinflammatory cytokines forming a cycle of activation of pathological pathways.

Figure 4

Four stages of extravasation of CD4+ T cells into the brain during health and disease. (a) In the capture stage, VCAM1 expressed on the endothelial cells binds to integrins expressed on CD4+ T cells. (b) After losing its speed, CD4+ T cells explore the surface of endothelial cells for ligands for their CCR7 receptor. (c) In the third stage known as adhesion, strong binds are formed using ICAM1 and VCAM1 from one side and LFA1 and α4β1 from the CD4+ T cells side. (d) Finally, paracellular diapedesis takes place, with cadherin downregulated, PECAM1 upregulated, and LRBC formed to store membrane proteins that takes an active part in the process. At the end of the process, LRBC is resorted, and sealing of the barrier takes place. Adapted from [35]. Copyright Springer, 2006.

Figure 5

The effect of known AD drugs on CD4+ interaction with the BBB in AD. While donepezil, rivastigmine, and memantine are capable of inhibiting Th1, only rivastigmine was reported to inhibit Th17. Galantamine could inhibit proliferation of CD4+ T cells; however, its specificity towards CD4+ T cell subpopulations is still obscure. Nevertheless, all four drugs are capable of decreasing adhesion of CD4+ T cells to the surface of endothelial cells through downregulating ICAM1. They are also capable of decreasing astrocytes activation. However, their ability to target astrocytes Th17 interaction is still open for investigation.

Figure 6

Repurposing old drugs to fight AD. Several strategies could be used to stop the progression of AD. SEW2871 could be used to confine CD4+ T cells into lymph nodes, while monoclonal antibodies could be used to reduce the number of CD4+ T cells. However, targeting Th17 through inhibition by avidin or P7C3 is more likely to decrease inflammation in the brain during AD. Sirukumab is an antibody against IL-6. Applying sirukumab could inhibit IL-6 production by astrocytes and hence decrease Th17 recruitment.