Distinct and Non-Redundant Roles of Microglia and Myeloid Subsets in Mouse Models of Alzheimer's Disease

Mildner, Alexander; Schlevogt, Bernhard; Kierdorf, Katrin; Böttcher, Chotima; Erny, Daniel; Kummer, Markus P.; Quinn, Michael C.; Brück, Wolfgang; Bechmann, Ingo; Heneka, Michael T.; Priller, Josef; Prinz, Marco

doi:10.1523/jneurosci.6209-10.2011

Cited by 298 publications

(295 citation statements)

References 53 publications

Supporting

Mentioning

270

Contrasting

Unclassified

Order By: Relevance

“…Blood-borne monocytes have been shown to infiltrate damaged or diseased brain tissue in animal models of other human neurological disease, such as the EAE model of multiple sclerosis (35), Alzheimer's disease (27,28,44), and traumatic brain injury (13,45). Previous studies have also reported elevated numbers of peripheral immune leukocytes after epileptiform activity (46,47).…”

Section: Discussionmentioning

confidence: 99%

“…A subclass of circulating monocytes expresses high levels of CCR2 (25), whereas microglia lack CCR2 expression (11). Notably, Ccr2 knockout mice display reduced recruitment of circulating monocytes into inflamed tissues, including the brain, in injury and disease animal models, such as traumatic brain injury (13,26), EAE models (14,15), and Alzheimer's disease (27,28).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Varvel

Neher

Bosch

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

288

291

View full text Add to dashboard Cite

The generalized seizures of status epilepticus (SE) trigger a series of molecular and cellular events that produce cognitive deficits and can culminate in the development of epilepsy. Known early events include opening of the blood-brain barrier (BBB) and astrocytosis accompanied by activation of brain microglia. Whereas circulating monocytes do not infiltrate the healthy CNS, monocytes can enter the brain in response to injury and contribute to the immune response. We examined the cellular components of innate immune inflammation in the days following SE by discriminating microglia vs. brain-infiltrating monocytes. Chemokine receptor 2 (CCR2 + ) monocytes invade the hippocampus between 1 and 3 d after SE. In contrast, only an occasional CD3 + T lymphocyte was encountered 3 d after SE. The initial cellular sources of the chemokine CCL2, a ligand for CCR2, included perivascular macrophages and microglia. The induction of the proinflammatory cytokine IL-1β was greater in FACS-isolated microglia than in brain-invading monocytes. However, Ccr2 knockout mice displayed greatly reduced monocyte recruitment into brain and reduced levels of the proinflammatory cytokine IL-1β in hippocampus after SE, which was explained by higher expression of the cytokine in circulating and brain monocytes in wild-type mice. Importantly, preventing monocyte recruitment accelerated weight regain, reduced BBB degradation, and attenuated neuronal damage. Our findings identify brain-infiltrating monocytes as a myeloid-cell subclass that contributes to neuroinflammation and morbidity after SE. Inhibiting brain invasion of CCR2 + monocytes could represent a viable method for alleviating the deleterious consequences of SE. myeloid cell heterogeneity | epileptogenesis | neuroprotection | seizure | microgliosis S tatus epilepticus (SE) is a serious medical emergency that triggers a series of cellular and molecular events that can result in the development of epilepsy, a chronic neurological disorder characterized by a persistently lowered seizure threshold (1). The early consequences of SE in rodents include a robust neuroinflammatory response, selective neuronal degeneration, and transient opening of the blood-brain barrier (BBB), leading to later cognitive decline. Although the neuroinflammatory features of SE in man are less well known, extravasation of albumin into the brain was observed for patients who died in SE (2), elevated cerebrospinal fluid levels of the cytokines IL-6, IL-8, and CXCL10 are typically found in patients with refractory SE compared with patients with other inflammatory neurologic disorders (3), and intense gliosis (both astrocytes and microglia) was observed in the temporal cortex of a patient with new-onset focal seizures that progressed to refractory SE (4). These admittedly sparse clinical findings are consistent with the much more extensive animal literature in demonstrating a florid inflammatory response of the brain to SE (5). We and others have provided evidence in animal models of epilepsy that quenching inflamma...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Varvel

Neher

Bosch

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

288

291

View full text Add to dashboard Cite

show abstract

“…Once activated, these cells can mediate progressive release of cytokines across the BBB and into the brain parenchyma (20). Finally, systemic administration of MPL may promote mobilization of microglial precursors from bone marrow, which move into the brain perivascular spaces and clear Aβ via phagocytosis (35,36).…”

Section: Discussionmentioning

confidence: 99%

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

Michaud

Hallé

Lampron

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

234

162

View full text Add to dashboard Cite

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...

show abstract

“…To obtain an infectivity-incubation time standard curve, 10-fold serial diluted brain homogenates used as the inocula of the Chandler and Obihiro strains were also injected into Tga 20 mice. The 50% lethal doses (LD 50 PrP-res detection by immunoblotting. For protease-resistant prion protein (PrP-res) detection, at 60, 90, and 120 dpi and at the terminal stage of the disease, brains were harvested and were homogenized in sterile PBS to prepare 10% (wt/vol) brain homogenates.…”

Section: Methodsmentioning

confidence: 99%

“…In AD model mice, bone marrow-derived microglia infiltrated from the peripheral circulation have protective potential against A␤ deposition and cognitive impairment in the early stage of the disease (47,48), although it is controversial whether the protective effect is due to a clearance of A␤ by microglia (49,50). However, it is also possible that at a later stage, increased A␤ production may overwhelm the microglial activity, or the proinflammatory milieu may decrease the phagocytic activity of microglia (51), or microglia may change the activation status to a more proinflammatory and neurotoxic phenotype (52).…”

Section: Prolonged Survival Of Prion-infected Cd14mentioning

confidence: 99%

Absence of CD14 Delays Progression of Prion Diseases Accompanied by Increased Microglial Activation

Sakai

Hasebe

Takahashi

et al. 2013

J Virol

View full text Add to dashboard Cite

Distinct and Non-Redundant Roles of Microglia and Myeloid Subsets in Mouse Models of Alzheimer's Disease

Cited by 298 publications

References 53 publications

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

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

Absence of CD14 Delays Progression of Prion Diseases Accompanied by Increased Microglial Activation

Contact Info

Product

Resources

About