Lampron et al. use a cuprizone mouse model of demyelination/remyelination to show that in CX3CR1-deficient mice, the clearance of myelin debris by microglia is impaired, affecting the integrity of axon and myelin sheaths.

The concept of the CNS as an immune-privileged organ has led to a common misunderstanding that it is not an active immunological organ, guarded from its surroundings by the blood-brain barrier (BBB). Recent advances in this field clearly demonstrate that the CNS is a highly immunologically active organ, with complex immune responses mostly based on innate immune processes. Such responses implicate a continuum of heterogeneous cell types both inside the CNS, in the periphery, and at their interface, the BBB. This Review aims to discuss the importance of the BBB as the first line of defense against brain infections and injuries of the CNS and the main molecular mechanisms involved in the control of the innate immune system of the CNS. We also review the central role of the neurovascular unit in diseases of the CNS and how it can be targeted for novel therapeutic strategies.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. The pathogenesis of this neurodegenerative disease, currently without curative treatment, is associated with the accumulation of amyloid β (Aβ) in brain parenchyma and cerebral vasculature. AD patients are unable to clear this toxic peptide, leading to Aβ accumulation in their brains and, presumably, the pathology associated with this devastating disease. Compounds that stimulate the immune system to clear Aβ may therefore have great therapeutic potential in AD patients. Monophosphoryl lipid A (MPL) is an LPS-derived Toll-like receptor 4 agonist that exhibits unique immunomodulatory properties at doses that are nonpyrogenic. We show here that repeated systemic injections of MPL, but not LPS, significantly improved AD-related pathology in APP swe /PS1 mice. MPL treatment led to a significant reduction in Aβ load in the brain of these mice, as well as enhanced cognitive function. MPL induced a potent phagocytic response by microglia while triggering a moderate inflammatory reaction. Our data suggest that the Toll-like receptor 4 agonist MPL may be a treatment for AD.lzheimer's disease (AD) is a neurodegenerative pathology characterized by the accumulation of amyloid beta (Aβ) and neurofibrillary tangles in the brain parenchyma (1). Inflammation, which occurs in parallel with the progression of the disease, is featured by the production of cytokines by activated microglia. The role of these cells in the pathogenesis of AD remains unclear and is an area of active investigation. Whereas chronic activation of microglial cells by Aβ can trigger the exaggerated release of cytokines and neurotoxic mediators that could be detrimental to neurons, microglia can also clear Aβ via increased phagocytosis and proteolytic degradation, which may be neuroprotective (2).Toll-like receptors (TLRs) on the surface of microglial cells have been shown to bind Aβ, which triggers downstream intracellular signaling cascades (3, 4). Microglia deficient in TLR2, TLR4, or the coreceptor CD14 are not activated by Aβ and do not exhibit a phagocytic response (5). Transgenic AD mice lacking TLR4 have markedly elevated levels of diffuse and fibrillar Aβ (3). Furthermore, stimulation of microglial cells with TLR2-, TLR4-, or TLR9-specific agonists accelerates Aβ clearance both in vitro and in vivo (3, 6, 7).Monophosphoryl lipid A (MPL) is a chemically detoxified lipid A moiety derived from Salmonella minnesota R595 LPS (8). This TLR4 ligand is at least 100-fold less pyrogenic than LPS yet maintains many of the immunomodulatory properties of LPS (9). Importantly, MPL is safe in humans and has been administered to millions of patients as a component of several vaccine formulations such as the Cervarix vaccine (10). We investigated herein the chronic use of the nonpyrogenic TLR4 agonist MPL and compared it with a strong TLR4 ligand (LPS) in a mouse model of AD.Although the therapeutic potential of innate immune activation for AD is being evaluated in preclinical models, this conc...