Antoine Lampron

Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer’s disease-related pathology

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 APPswe/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.

Innate Immunity in the CNS: Redefining the Relationship between the CNS and Its Environment

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.

Inefficient clearance of myelin debris by microglia impairs remyelinating processes

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.

Migration of Bone Marrow-Derived Cells Into the Central Nervous System in Models of Neurodegeneration

Microglia are the brain‐resident macrophages tasked with the defense and maintenance of the central nervous system (CNS). The hematopoietic origin of microglia has warranted a therapeutic potential for the hematopoietic system in treating diseases of the CNS. However, migration of bone marrow‐derived cells (BMDC) into the CNS is a marginal event under normal, healthy conditions. A busulfan‐based chemotherapy regimen was used for bone marrow transplantation in wild‐type mice before subjecting them to a hypoxic–ischemic brain injury or in APP/PS1 mice prior to the formation of amyloid plaques. The cells were tracked and analyzed throughout the development of the pathology. The efficacy of a preventive macrophage colony‐stimulating factor (M‐CSF) treatment was also studied to highlight the effects of circulating monocytes in hypoxic–ischemic brain injury. Such an injury induces a strong migration of BMDC into the CNS, without the need for irradiation. These migrating cells do not replace the entire microglial pool but rather are confined to the sites of injury for several weeks, suggesting that they could perform specific functions. M‐CSF showed neuroprotective effects as a preventive treatment. In APP/PS1 mice, the formation of amyloid plaques was sufficient to induce the entry of cells into the parenchyma, though in low numbers. This study confirms that BMDC infiltrate the CNS in animal models for stroke and Alzheimers disease and that peripheral cells can be targeted to treat affected regions of the CNS. J. Comp. Neurol. 521:3863–3876, 2013.

Effects of Myeloablation, Peripheral Chimerism, and Whole-Body Irradiation on the Entry of Bone Marrow-Derived Cells into the Brain:

Understanding how bone marrow-derived cells (BMDCs) enter the central nervous system (CNS) is critical for the development of therapies for brain-related disorders using hematopoietic stem cells. We investigated the brain damages and blood–brain barrier (BBB) modification following either whole-body irradiation or a myeloablative chemotherapy regimen in mice, and the capacity for these treatments to induce the entry of BMDCs into the CNS. Neither treatment had a lasting effect on brain integrity and both were equally efficient at achieving myeloablation. Injection of bone marrow cells from green fluorescent protein (GFP) transgenic mice was able to completely repopulate the hematopoietic niche in the circulation and in hematopoietic organs (thymus and spleen). However, GFP+ cells only entered the brain following whole-body irradiation. We conclude that myeloablation, damages to the brain integrity, or the BBB and peripheral chimerism are not responsible for the entry of BMDCs into the CNS following irradiation.

Tissue-Plasminogen Activator Attenuates Alzheimer's Disease-Related Pathology Development in APPswe/PS1 Mice.

Alzheimer’s disease (AD) is the leading cause of dementia among elderly population. AD is characterized by the accumulation of beta-amyloid (Aβ) peptides, which aggregate over time to form amyloid plaques in the brain. Reducing soluble Aβ levels and consequently amyloid plaques constitute an attractive therapeutic avenue to, at least, stabilize AD pathogenesis. The brain possesses several mechanisms involved in controlling cerebral Aβ levels, among which are the tissue-plasminogen activator (t-PA)/plasmin system and microglia. However, these mechanisms are impaired and ineffective in AD. Here we show that the systemic chronic administration of recombinant t-PA (Activase rt-PA) attenuates AD-related pathology in APPswe/PS1 transgenic mice by reducing cerebral Aβ levels and improving the cognitive function of treated mice. Interestingly, these effects do not appear to be mediated by rt-PA-induced plasmin and matrix metalloproteinases 2/9 activation. We observed that rt-PA essentially mediated a slight transient increase in the frequency of patrolling monocytes in the circulation and stimulated microglia in the brain to adopt a neuroprotective phenotype, both of which contribute to Aβ elimination. Our study unraveled a new role of rt-PA in maintaining the phagocytic capacity of microglia without exacerbating the inflammatory response and therefore might constitute an interesting approach to stimulate the key populations of cells involved in Aβ clearance from the brain.

Targeting the hematopoietic system for the treatment of Alzheimer's disease.

Alzheimers disease (AD) is the most prevalent cause of dementia in humans. This disease is characterized by the presence of amyloid beta (Ab) deposits in the parenchyma (also known as amyloid plaques or senile plaques) and in the cerebral vasculature. Though Ab formation and deposits are strongly correlated with cognitive impairment, the mechanisms responsible for the synaptic dysfunctions and loss of neurons in AD remain largely unknown. Many studies have provided evidence that microglial cells are attracted to amyloid deposits both in human samples and in rodent transgenic models that develop this disease. We have recently found that blood-derived microglia and not their resident counterparts have the ability to eliminate amyloid deposits by a cell-specific phagocytic mechanism. These bone marrow-derived microglia have consequently a great therapeutic potential for AD patients. Molecular strategies aiming to improve their recruitment could lead to a new powerful tool for the elimination of toxic Ab and improve cognitive functions. However, numerous limitations have to be taken into consideration before recommending such a cellular therapy and these are discussed in the present review.

Bone Marrow Chimeras to Study Neuroinflammation

Bone marrow transplantation is the standard of care for a host of diseases such as leukemia and multiple myeloma, as well as genetically inherited metabolic diseases affecting the central nervous system. In mouse models, bone marrow transplantation has proven a valuable tool for understanding the hematopoietic system and the homing of hematopoietic cells to their target organs. Many techniques have been developed to create chimeric mice, animals with a hematopoietic system derived from a genetic background that differs from the rest of the body. Current genetic tools allow for virtually limitless possibilities in the choice of donor mice. This protocol describes methods of bone marrow transplantation in mouse models for studies of the brain under basal and pathological conditions. Specific points to be addressed include the preparation of recipient mice by irradiation or chemotherapy; the choice, isolation, and injection of donor cells; and analytical methods such as fluorescence‐activated cell sorting and immunostaining.

Targeting the hematopoietic system to treat Alzheimer's disease

kg/day) or control diet for 16 weeks. Thereafter, mice were transcardially perfused and pial-arteries surgically removed. Arterial proteins were extracted, trypsin-digested, fractionated by strong cation exchange (gel-free-method) and 1D SDS-PAGE (gel-based-method), and analyzed by nanoLC-MS/MS using nanoAcquity UPLC (Waters) and ESI-LTQ Orbitrap (Thermo). Protein identification was performed using Mascot. MatchRx software was used for alignment and quantification across the multiple samples, and peptide intensity validation was performed using MSight. Differentially-expressed proteins were identified at 1.5 and 2 fold-changes, and at p 0.05 and p 0.01. Three biological and two technical replicates were conducted. Results: We identified 6,566 pial-arterial proteins, of which 975 (15%) were differentially-expressed between WT and APP mice at fold-change 1.5 and p 0.05. The altered proteins were associated with biological pathways related to amyloidosis, oxidative stress and vasomotricity, as well as processes over-represented in the AlzGene database. A more stringent criteria ( 2.0-fold, p 0.01) identified 94 robustly differentially-expressed proteins. Of these, 72 were modulated by pioglitazone-treatment, with 61% showing the same expressions levels as WT, and 39% showing partial-normalization. 20% of these proteins had known PPRE elements and/or were known responders to pioglitazone. Conclusions: We demonstrated that increased soluble Ab adversely impacts the cerebrovascular proteome. Pioglitazone-mediated functional rescue of the cerebrovasculature is associated with normalization of the majority of altered proteins in the vessel wall, particularly those related to oxidative stress and inflammation.