Apolipoprotein J/clusterin limits the severity of murine autoimmune myocarditis

McLaughlin, Lea; Zhu, Guijin; Mistry, Meenakshi J.; Ley-Ebert, Cathy; Stuart, William D.; Florio, Carolyn J.; Groen, Pamela A.; Witt, Sandra A.; Kimball, Thomas R.; Witte, David P.; Harmony, Judith A.K.; Aronow, Bruce J.

doi:10.1172/jci9037

Cited by 190 publications

(164 citation statements)

References 55 publications

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“…33 Together these observations suggest that the increased expression of clusterin in AD may represent a protective effect. In further support of its pro-and antiapoptotic effects, studies using cluÀ/À mice, demonstrate that autoimmune myocardial damage is increased 34 and clusterin has neuroprotective properties in permanent focal cerebral ischemia. 35 In contrast, in the same knockout strain the absence of clusterin reduces cell death in neonatal hypoxia-ischaemia via a caspase-3-independent brain injury pathway, 36 suggesting it functions to exacerbate neuronal damage under these circumstances.…”

Section: Discussionmentioning

confidence: 89%

Clusterin secreted by astrocytes enhances neuronal differentiation from human neural precursor cells

Cordero-Llana

Scott²,

Maslen

et al. 2011

Cell Death Differ

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Neuronal differentiation from expanded human ventral mesencephalic neural precursor cells (NPCs) is very limited. Astrocytes are known to secrete neurotrophic factors, and so in order to enhance neuronal survival from NPCs, we tested the effect of regional astrocyte-conditioned medium (ACM) from the rat cortex, hippocampus and midbrain on this process. Human NPC's were expanded in FGF-2 before differentiation for 1 or 4 weeks in ACM. The results show that ACM from the hippocampus and midbrain increase the number of neurons from expanded human NPCs, an effect that was not observed with cortical ACM. In addition, both hippocampal and midbrain ACM increased the number and length of phosphorylated neurofilaments. MALDI-TOF analysis used to determine differences in media revealed that although all three regional ACMs had cystatin C, a-2 macroglobulin, extracellular matrix glycoprotein and vimentin, only hippocampal and midbrain ACM also contained clusterin, which when immunodepleted from midbrain ACM eliminated the observed effects on neuronal differentiation. Furthermore, clusterin is a highly glycosylated protein that has no effect on cell proliferation but decreases apoptotic nuclei and causes a sustained increase in phosphorylated extracellular signalregulated kinase, implicating its role in cell survival and differentiation. These findings further reveal differential effects of regional astrocytes on NPC behavior and identify clusterin as an important mediator of NPC-derived neuronal survival and differentiation. Cell Death and Differentiation (2011) 18, 907-913; doi:10.1038/cdd.2010.169; published online 7 January 2011Astrocytes are essential regulators of neuronal function, and produce diffusible and non-diffusible neuron supporting signals, including neurotrophic factors and membrane-bound molecules (for review see Barres 1 ). Interestingly, emerging evidence highlights that there are many regional differences in astrocytes in respect to structure and function and soluble factor production, for example, astrocytes from the hippocampus and their conditioned media can support the survival of neurons from regions other than the hippocampus. 2 In contrast, astrocytes from the mesencephalon release factors, which are more effective at promoting dopamine neuron survival than cortical or striatal astrocytes. 3 These studies show that the astrocytes from neurogenic regions 4 release more neurogenic factors than astrocytes from the non-neurogenic regions.It is well established that stem cells can be isolated from the developing and adult rodent CNS, and expanded in vitro using EGF and FGF2 (for review see Gage 5 ) More recently the same has been shown to be true for the developing human fetal CNS. 6 These cells are capable of long-term expansion in vitro to achieve B50 population doublings. 6 However, as they progress in culture with time, their differentiation pattern changes with the number of neurons declining and the number of astrocytes predominating. 7 Previous studies have shown that astrocyte-conditioned medi...

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Section: Discussionmentioning

confidence: 89%

Clusterin secreted by astrocytes enhances neuronal differentiation from human neural precursor cells

Cordero-Llana

Scott²,

Maslen

et al. 2011

Cell Death Differ

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“…Whether apoAI and clusterin play a role in CNS lipid metabolism, or in normal brain function, is not clear. Genetic deficiency of either protein in humans or mice does not result in an obvious CNS phenotype (Schaefer et al 1982;McLaughlin et al 2000). Interestingly, single-nucleotide polymorphisms in clusterin have been shown to be a risk factor for AD (Harold et al 2009;Lambert et al 2009).…”

Section: Neurobiology Of Apoementioning

confidence: 99%

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Holtzman

Herz²,

2012

Cold Spring Harbor Perspectives in Medicine

673

602

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“…After myosin-induced auto-immune myocarditis, cell damage is also more severe in clusterin-deficient mice [133] and post-ischemic brain injury is more severe [134]. Together this data suggests that stress-induced increase in clusterin expression is a cytoprotective response.…”

Section: Evidence For In Vivo Chaperone Action/disease Involvementmentioning

confidence: 75%

Extracellular Chaperones

Dabbs

Wyatt

Yerbury

et al. 2011

Topics in Current Chemistry

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The maintenance of the levels and correct folding state of proteins (proteostasis) is a fundamental prerequisite for life. Life has evolved complex mechanisms to maintain proteostasis and many of these that operate inside cells are now well understood. The same cannot yet be said of corresponding processes in extracellular fluids of the human body, where inappropriate protein aggregation is known to underpin many serious diseases such as Alzheimer's disease, type II diabetes and prion diseases. Recent research has uncovered a growing family of abundant extracellular chaperones in body fluids which appear to selectively bind to exposed regions of hydrophobicity on misfolded proteins to inhibit their toxicity and prevent them from aggregating to form insoluble deposits. These extracellular chaperones are also implicated in clearing the soluble, stabilized misfolded proteins from body fluids via receptor-mediated endocytosis for subsequent lysosomal degradation. Recent work also raises the possibility that extracellular chaperones may play roles in modulating the immune response. Future work will better define the in vivo functions of extracellular chaperones in proteostasis and immunology and pave the way for the development of new treatments for serious diseases.

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Apolipoprotein J/clusterin limits the severity of murine autoimmune myocarditis

Cited by 190 publications

References 55 publications

Clusterin secreted by astrocytes enhances neuronal differentiation from human neural precursor cells

Clusterin secreted by astrocytes enhances neuronal differentiation from human neural precursor cells

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Extracellular Chaperones

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