The microglial phagocytic role with specific plaque types in the Alzheimer disease brain

D’Andrea, Michael R.; Cole, Gregory M.; Ard, March D.

doi:10.1016/j.neurobiolaging.2003.12.026

Cited by 195 publications

(142 citation statements)

References 69 publications

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“…Because a significant amyloid load is already present at the time of earliest clinical symptoms (Lopresti et al, 2005), a therapeutic approach that addresses the deleterious effects of existing amyloid deposits is essential (Schenk, 2002). Although the production of ␤-amyloid (A␤), the fibrillary component of amyloid plaques, is thought to be primarily neuronal (Goedert, 1987;Calhoun et al, 1999), it is the microglial cells that react to amyloid as to other brain injuries, and microglia have been shown to have the ability to phagocytose A␤, at least in culture (Bard et al, 2000;Rogers et al, 2002;D'Andrea et al, 2004;Frackowiak et al, 2005). Indeed, the most successful of the amyloid clearing therapies, immunization, has been indirectly linked to microglial activation (Hardy and Selkoe, 2002;Wilcock et al, 2004;Barger, 2005).…”

Section: Introductionmentioning

confidence: 99%

Dynamics of the Microglial/Amyloid Interaction Indicate a Role in Plaque Maintenance

Bolmont¹,

Haiss²,

Eicke³

et al. 2008

J. Neurosci.

429

401

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Microglial cells aggregate around amyloid plaques in Alzheimer's disease, but, despite their therapeutic potential, various aspects of their reactive kinetics and role in plaque pathogenesis remain hypothetical. Through use of in vivo imaging and quantitative morphological measures in transgenic mice, we demonstrate that local resident microglia rapidly react to plaque formation by extending processes and subsequently migrating toward plaques, in which individual transformed microglia somata remain spatially stable for weeks. The number of plaque-associated microglia increased at a rate of almost three per plaque per month, independent of plaque volume. Larger plaques were surrounded by larger microglia, and a subset of plaques changed in size over time, with an increase or decrease related to the volume of associated microglia. Far from adopting a more static role, plaque-associated microglia retained rapid process and membrane movement at the plaque/glia interface. Microglia internalized systemically injected amyloid-binding dye at a much higher rate in the vicinity of plaques. These results indicate a role for microglia in plaque maintenance and provide a model with multiple targets for therapeutic intervention.

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Section: Introductionmentioning

confidence: 99%

Dynamics of the Microglial/Amyloid Interaction Indicate a Role in Plaque Maintenance

Bolmont¹,

Haiss²,

Eicke³

et al. 2008

J. Neurosci.

429

401

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“…In the AD brain, activated microglia are found in the direct vicinity of Aβ plaques (D'Andrea et al, 2004;Itagaki et al, 1989). Initially, they take on a neuroprotective role by releasing amyloid-degrading enzymes for the clearance of amyloid fibrils in the early stages of the disease.…”

Section: Supplementary Introductionmentioning

confidence: 99%

Imaging microglial activation and glucose consumption in a mouse model of Alzheimer's disease

Rapic

Backes

Viel

et al. 2013

Neurobiology of Aging

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Abstract. In Alzheimer´s disease (AD), persistent microglial activation as sign of chronic neuroinflammation contributes to disease progression. Our study aimed to in vivo visualize and quantify microglial activation in 13-to 15-month-old AD mice using [ 11 C]-(R)-PK11195 and positron emission tomography (PET). We attempted to modulate neuroinflammation by subjecting the animals to an anti-inflammatory treatment with pioglitazone (5-weeks' treatment, 5-week wash-out period).[ 11 C]-(R)-PK11195 distribution volume values in AD mice were significantly higher compared with control mice after the wash-out period at 15 months, which was supported by immunohistochemistry data. However, [ 11 C]-(R)-PK11195 µPET could not demonstrate genotype-or treatment-dependent differences in the 13-to 14 month-old animals, suggesting that microglial activation in AD mice at this age and disease stage is too mild to be detected by this imaging method.Introduction. In AD, activated microglia are found in the direct vicinity of amyloid β (Aβ) plaques.

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“…We have shown that blood-borne monocyte/ macrophages of AD patients migrate across the blood-brain barrier into AD brain but are defective in clearance of A␤ in neuritic plaques (4), and they overexpress cyclooxygenase-2 and inducible NO synthase (4). Resident microglia in AD brain display markers of inflammation (5,6), phagocytosis (7), and proinflammatory but not prophagocytic genes (8). However, most microglia invading A␤ plaques in transgenic mouse models are bone marrow-derived, not resident microglia (9).…”

mentioning

confidence: 99%

Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin

Fiala

Liu²,

Espinosa‐Jeffrey

et al. 2007

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

207

251

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We have tested a hypothesis that the natural product curcuminoids, which has epidemiologic and experimental rationale for use in AD, may improve the innate immune system and increase amyloid-␤ (A␤) clearance from the brain of patients with sporadic Alzheimer's disease (AD). Macrophages of a majority of AD patients do not transport A␤ into endosomes and lysosomes, and AD monocytes do not efficiently clear A␤ from the sections of AD brain, although they phagocytize bacteria. In contrast, macrophages of normal subjects transport A␤ to endosomes and lysosomes, and monocytes of these subjects clear A␤ in AD brain sections. Upon A␤ stimulation, mononuclear cells of normal subjects up-regulate the transcription of ␤-1,4-mannosyl-glycoprotein 4-␤-N-acetylglucosaminyltransferase (MGAT3) (P < 0.001) and other genes, including Toll like receptors (TLRs), whereas mononuclear cells of AD patients generally down-regulate these genes. Defective phagocytosis of A␤ may be related to down-regulation of MGAT3, as suggested by inhibition of phagocytosis by using MGAT3 siRNA and correlation analysis. Transcription of TLR3, bditTLR4, TLR5, bditTLR7, TLR8, TLR9, and TLR10 upon A␤ stimulation is severely depressed in mononuclear cells of AD patients in comparison to those of control subjects. In mononuclear cells of some AD patients, the curcuminoid compound bisdemethoxycurcumin may enhance defective phagocytosis of A␤, the transcription of MGAT3 and TLRs, and the translation of TLR2-4. Thus, bisdemethoxycurcumin may correct immune defects of AD patients and provide a previously uncharacterized approach to AD immunotherapy.amyloid-␤ ͉ phagocytosis ͉ endocytosis ͉ MGAT3 siRNA A ccording to the amyloid-␤ (A␤) hypothesis, amyloidosis occurring in the brain of patients with Alzheimer's disease (AD) by fibrillar A␤ 1-42 and 1-40 (1) and A␤ oligomers (2) is a leading cause of neurodegeneration in AD (3). Macrophages and microglia are the innate immune cells responsible for clearance of pathogens and waste products. We have shown that blood-borne monocyte/ macrophages of AD patients migrate across the blood-brain barrier into AD brain but are defective in clearance of A␤ in neuritic plaques (4), and they overexpress cyclooxygenase-2 and inducible NO synthase (4). Resident microglia in AD brain display markers of inflammation (5, 6), phagocytosis (7), and proinflammatory but not prophagocytic genes (8). However, most microglia invading A␤ plaques in transgenic mouse models are bone marrow-derived, not resident microglia (9). Thus, the brains of AD patients and transgenic mice seem to display inflammatory responses by microglia and defective A␤ clearance by blood-borne macrophages. Consequently, the defective innate immune system of AD patients might be a culprit in brain amyloidosis leading to brain inflammation.The mechanisms of neurodegeneration produced by abnormally folded proteins, A␤, and phosphorylated remain an enigma (10).The pathogenesis of neurodegeneration in AD involves the impact of polymorphic proteins, such as amyloid precursor...

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The microglial phagocytic role with specific plaque types in the Alzheimer disease brain

Cited by 195 publications

References 69 publications

Dynamics of the Microglial/Amyloid Interaction Indicate a Role in Plaque Maintenance

Dynamics of the Microglial/Amyloid Interaction Indicate a Role in Plaque Maintenance

Imaging microglial activation and glucose consumption in a mouse model of Alzheimer's disease

Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin

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