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MyD88 deficiency ameliorates ?-amyloidosis in an animal model of Alzheimer's disease.

ABSTRACT: The accumulation of ?-amyloid protein (A?) in the brain is thought to be a primary etiologic event in Alzheimer's disease (AD). Fibrillar A? plaques, a hallmark of AD abnormality, are closely associated with activated microglia. Activated microglia have contradictory roles in the pathogenesis of AD, being either neuroprotective (by clearing harmful A? and repairing damaged tissues) or neurotoxic (by producing proinflammatory cytokines and reactive oxygen species). A? aggregates can activate microglia by interacting with multiple toll-like receptors (TLRs), the pattern-recognition receptors of the innate immune system. Because the adapter protein MyD88 is essential for the downstream signaling of all TLRs, except TLR3, we investigated the effects of MyD88 deficiency (MyD88(-/-)) on A? accumulation and microglial activation in an AD mouse model. MyD88 deficiency decreased A? load and microglial activation in the brain. The decrease in A? load in an MyD88(-/-) AD mouse model was associated with increased and decreased protein expression of apolipoprotein E (apoE) and CX3CR1, respectively, compared with that in an MyD88 wild-type AD mouse model. These results suggest that MyD88 deficiency may reduce A? load by enhancing the phagocytic capability of microglia through fractalkine (the ligand of CX3CR1) signaling and by promoting apoE-mediated clearance of A? from the brain. These findings also suggest that chronic inflammatory responses induced by A? accumulation via the MyD88-dependent signaling pathway exacerbate ?-amyloidosis in AD.

SUBMITTER: Lim JE

PROVIDER: S-EPMC3157279 | biostudies-other | 2011 Sep

REPOSITORIES: biostudies-other

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MyD88 deficiency ameliorates β-amyloidosis in an animal model of Alzheimer's disease.

Lim Jeong-Eun JE Kou Jinghong J Song Min M Pattanayak Abhinandan A Jin Jingji J Lalonde Robert R Fukuchi Ken-ichiro K

The American journal of pathology 20110719 3

The accumulation of β-amyloid protein (Aβ) in the brain is thought to be a primary etiologic event in Alzheimer's disease (AD). Fibrillar Aβ plaques, a hallmark of AD abnormality, are closely associated with activated microglia. Activated microglia have contradictory roles in the pathogenesis of AD, being either neuroprotective (by clearing harmful Aβ and repairing damaged tissues) or neurotoxic (by producing proinflammatory cytokines and reactive oxygen species). Aβ aggregates can activate micr ...[more]

PMID: 21763676

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Project description:Reduced cerebral blood flow impairs cognitive function and ultimately causes irreparable damage to brain tissue. The gliovascular unit, composed of neural and vascular cells, assures sufficient blood supply to active brain regions. Astrocytes, vascular smooth muscle cells, and pericytes are important players within the gliovascular unit modulating vessel diameters. While the importance of the gliovascular unit and the signals involved in regulating local blood flow to match neuronal activity is now well recognized, surprisingly little is known about this interface in disease. Alzheimer's disease is associated with reduced cerebral blood flow. Here, we studied how the gliovascular unit is affected in a mouse model of Alzheimer's disease, using a combination of ex vivo and in vivo imaging approaches. We specifically labelled vascular amyloid in living mice using the dye methoxy-XO4. We elicited vessel responses ex vivo using either pharmacological stimuli or cell-specific calcium uncaging in vascular smooth muscle cells or astrocytes. Multi-photon in vivo imaging through a cranial window allowed us to complement our ex vivo data in the presence of blood flow after label-free optical activation of vascular smooth muscle cells in the intact brain. We found that vascular amyloid deposits separated astrocyte end-feet from the endothelial vessel wall. High-resolution 3D images demonstrated that vascular amyloid developed in ring-like structures around the vessel circumference, essentially forming a rigid cast. Where vascular amyloid was present, stimulation of astrocytes or vascular smooth muscle cells via ex vivo Ca(2+) uncaging or in vivo optical activation produced only poor vascular responses. Strikingly, vessel segments that were unaffected by vascular amyloid responded to the same extent as vessels from age-matched control animals. We conclude that while astrocytes can still release vasoactive substances, vascular amyloid deposits render blood vessels rigid and reduce the dynamic range of affected vessel segments. These results demonstrate a mechanism that could account in part for the reduction in cerebral blood flow in patients with Alzheimer's disease.media-1vid110.1093/brain/awv327_video_abstractawv327_video_abstract.

Dataset Information

MyD88 deficiency ameliorates ?-amyloidosis in an animal model of Alzheimer's disease.

Publications

MyD88 deficiency ameliorates β-amyloidosis in an animal model of Alzheimer's disease.

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