T Lymphocytes and Inflammatory Mediators in the Interplay between Brain and Blood in Alzheimer's Disease: Potential Pools of New Biomarkers

Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the main cause of dementia. The disease is among the leading medical concerns of the modern world, because only symptomatic therapies are available, and no reliable, easily accessible biomarkers exist for AD detection and monitoring. Therefore extensive research is conducted to elucidate the mechanisms of AD pathogenesis, which seems to be heterogeneous and multifactorial. Recently much attention has been given to the neuroinflammation and activation of glial cells in the AD brain. Reports also highlighted the proinflammatory role of T lymphocytes infiltrating the AD brain. However, in AD molecular and cellular alterations involving T cells and immune mediators occur not only in the brain, but also in the blood and the cerebrospinal fluid (CSF). Here we review alterations concerning T lymphocytes and related immune mediators in the AD brain, CSF, and blood and the mechanisms by which peripheral T cells cross the blood brain barrier and the blood-CSF barrier. This knowledge is relevant for better AD therapies and for identification of novel biomarkers for improved AD diagnostics in the blood and the CSF. The data will be reviewed with the special emphasis on possibilities for development of AD biomarkers.

Figure 1

Aβ transport across the blood brain barrier (BBB) in Alzheimer disease. In Alzheimer disease the loosing of tight junctions leads to increased BBB permeability. In healthy conditions the Aβ peptide is transported to the brain by the receptor for advanced glycosylation products (RAGE) and cleared from the brain to the blood by LDL-Receptor-Proteins (LRPs) followed by p-glycoprotein (P-gp). In Alzheimer's disease these transport systems are impaired: the expression of RAGE is increased and the expression of LRPs is decreased, leading to the accumulation of Aβ in the brain.

Figure 2

T lymphocytes migration at the blood brain barrier (BBB) in AD. The key role of the BBB is defending the brain against the harmful influence of peripheral factors. In AD the permeability of the BBB is increased, and the migration of peripheral immune cells contributes to the progress of neuroinflammation in the brain. In response to Aβ stimulation from the parenchyma, the transmigration of immune cells from the blood into the brain is mediated by VCAM-1. At postcapillary vessels the immune cells cross the BBB upon interaction with the CX3CR1 receptor on endothelial cells. Other key mediators of the immune cells' migration are the RAGE receptor and the CCR5 chemokine receptor. Moreover, Aβ activates microglial cells to produce TNF-α, which can promote transendothelial migration of T cells and has the ability to enable astroglial cells' activation and overproduction of TGF-β1, which in turn may lead to decreased Aβ plaque loads.

Figure 3

T lymphocytes infiltration and inflammatory mediators at the blood-cerebrospinal fluid barrier (BCSFB) in AD. The BCSFB is a selective barrier that restricts the passages of circulating immune cells from the stroma compartment into the brain parenchyma. In AD the BCSFB is impaired and T cells migrating through the BCSFB produce inflammatory mediators which are associated with the immune response to pathological conditions. At the BCSFB the chemokine CCL11 is produced in response to IL-4 secreted from Th2 cells and can be inhibited by IFN-γ secreted from Th1 cells. In the CSF in AD the increased levels of cytokines: TNF-α, IL-6, IL-8, chemokines: CXCL8, CCL11, and CCL2, and cytokine receptors: sIL-6R, TIMP-1, and TNFR-I are observed. Moreover, enhanced expression of ICAM-1, VCAM-1, and P-selectin in the CPE leads to the damage of tight junctions and modulates immune cell migration to the CSF. Additional explanations can be found in the article text. Bold arrows indicate regulation of molecule levels [↑, upregulation, ↓, downregulation]. Blue arrows indicate affected processes.