Abstract
Neurodegenerative diseases are closely related to inflammatory and autoimmune events, suggesting that the dysregulation of the immune system is a key pathological factor. Both multiple sclerosis (MS) and Alzheimer's disease (AD) are characterized by infiltrating immune cells, activated microglia, astrocyte proliferation, and neuronal damage. Moreover, MS and AD share a common pro-inflammatory signature, characterized by peripheral leukocyte activation and transmigration to the central nervous system (CNS). MS and AD are both characterized by the accumulation of activated neutrophils in the blood, leading to progressive impairment of the blood–brain barrier. Having migrated to the CNS during the early phases of MS and AD, neutrophils promote local inflammation that contributes to pathogenesis and clinical progression. The role of circulating T cells in MS is well-established, whereas the contribution of adaptive immunity to AD pathogenesis and progression is a more recent discovery. Even so, blocking the transmigration of T cells to the CNS can benefit both MS and AD patients, suggesting that common adaptive immunity mechanisms play a detrimental role in each disease. There is also growing evidence that regulatory T cells are beneficial during the initial stages of MS and AD, supporting the link between the modulatory immune compartments and these neurodegenerative disorders. The number of resting regulatory T cells declines in both diseases, indicating a common pathogenic mechanism involving the dysregulation of these cells, although their precise role in the control of neuroinflammation remains unclear. The modulation of leukocyte functions can benefit MS patients, so more insight into the role of peripheral immune cells may reveal new targets for pharmacological intervention in other neuroinflammatory and neurodegenerative diseases, including AD.
Highlights
Multiple sclerosis (MS) and Alzheimer’s disease (AD) are two of the most widely studied central nervous system (CNS) pathologies
The same phenomenon has been observed in AD mice, where the loss of CCR2 reduces the number of monocytic phagocytes in the brain [67, 68] (Figure 1, Table 2). These findings suggest that classical monocytes are the main subset that invades the CNS in neuroinflammatory conditions such as MS and AD and that CCR2 plays a fundamental role in the recruitment of these cells into the CNS
One clear example of such a shared molecular mechanism is represented by α4 integrins, which can be targeted in both MS and AD
Summary
Multiple sclerosis (MS) and Alzheimer’s disease (AD) are two of the most widely studied central nervous system (CNS) pathologies. Immune cell trafficking has been documented in AD and was shown to be detrimental in transgenic mice with ADlike disease [10, 11] Neuroinflammation in both MS and AD is characterized by the activation of microglia and astrocytes, leading to the secretion of pro-inflammatory cytokines and chemokines that recruit more immune cells from the periphery to the CNS [12, 13]. The specialized pro-resolving lipid mediators, which mediate inflammation resolution and reduce neutrophil and monocytes infiltration into the brain, are impaired in MS and AD patients and their levels correlate with disease severity [14,15,16] These defects in the resolution pathways further emphasize the common detrimental role of peripheral immune cells in the maintenance of neuroinflammatory process in MS and AD. The blocking or inhibition of neutrophil activity could achieve therapeutic benefits for both MS and AD patients (Figure 1)
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