Cystatin C is released in association with exosomes: A new tool of neuronal communication which is unbalanced in Alzheimer's disease

Ghidoni, Roberta; Paterlini, Anna; Albertini, Valentina; Glionna, Michela; Monti, Eugenio; Schiaffonati, Luisa; Benussi, Luisa; Levy, Efrat; Binetti, Giuliano

doi:10.1016/j.neurobiolaging.2009.08.013

Cited by 101 publications

(79 citation statements)

References 33 publications

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“…It has been previously shown that a fraction of intracellular Ab can be released through exosomes by neurons and oligodendrocytes. 32,[45][46][47] In addition, phagocytosed Ab has been found to be re-secreted from microglia, although through an undefined mechanism. 48 We now show that microglia release neurotoxic Ab 1-42 and Ab 1-40 species in association with MVs.…”

Section: Discussionmentioning

confidence: 99%

Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles

et al. 2013

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Alzheimer's disease (AD) is characterized by extracellular amyloid-b (Ab) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that soluble pre-fibrillar Ab species, rather than insoluble fibrils, are the most toxic forms of Ab. Preventing soluble Ab formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble Ab species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic Ab forms trafficked to MVs after Ab internalization into microglia. MV neurotoxicity was neutralized by the Ab-interacting protein PrP and anti-Ab antibodies, which prevented binding to neurons of neurotoxic soluble Ab species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease. Cell Death and Differentiation (2014) 21, 582-593; doi:10.1038/cdd.2013.180; published online 13 December 2013Alzheimer's disease (AD) is the major cause of dementia in humans. Neuronal loss and cognitive decline occurring in AD patients are traditionally linked to the accumulation in the brain of extracellular plaques consisting of short amyloid-b (Ab) peptides of 39-42 amino acids, generated by amyloidogenic cleavage of the amyloid precursor protein. 1 Among Ab peptides, Ab 1-42 and pyroglutamate-modified Ab very rapidly aggregate and initiate the complex multistep process that leads to mature fibrils and plaque. 2,3 Although association of amyloid plaques with AD has long been assumed, Ab load does not correlate with neuronal loss 4,5 and high plaque burden does not necessarily lead to dementia in humans. 6,7 Accordingly, recent evidence clearly showed that the amyloid load reaches a plateau early after the onset of clinical symptoms in AD patients 8 and does not substantially increase in size during clinical progression. 9 These observations agree with the current view that small, soluble pre-fibrillar Ab species, rather than plaques formed by insoluble Ab fibrils, are the most toxic forms of Ab. 10 These cause synaptic dysfunction and spine loss, and correlate most closely with the severity of human AD. 5,8,11 Recent biochemical studies indicated that natural sphingolipids and gangliosides, whose metabolism has been shown to be altered in AD patients, 12 destabilize and rapidly resolubilize long Ab fibrils to neurotoxic species. 13 These studies also showed that phospholipids stabilize toxic oligomers...

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Section: Discussionmentioning

confidence: 99%

Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles

et al. 2013

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“…Extracellular vesicles can be formed by budding from plasma membrane, or originated from multivesicular endosomes or multivesicular bodies (MVBs) (Tkach and Thery 2016). Neurons can release exosomes that contain functionally active proteins and miRNAs, which can exert a neuroprotective or neurotoxic role (Ghidoni et al 2011; Janas et al 2016; Lachenal et al 2011; Morel et al 2013). Recent several reviews offer the roles of exosomes and microvesicles in normal function, the development of regeneration of CNS as well as in the onset and progression of of some neurodegenerative and neuroinflammatory diseases (Janas et al 2016; Porro et al 2015).…”

Section: Endogenous Protective Mechanisms and Secreted Help-me Sigmentioning

confidence: 99%

Help-me signaling: Non-cell autonomous mechanisms of neuroprotection and neurorecovery

Xing

2017

Progress in Neurobiology

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Self-preservation is required for life. At the cellular level, this fundamental principle is expressed in the form of molecular mechanisms for preconditioning and tolerance. When the cell is threatened, internal cascades of survival signaling become triggered to protect against cell death and defend against future insults. Recently, however, emerging findings suggest that this principle of self-preservation may involve not only intracellular signals; the release of extracellular signals may provide a way to recruit adjacent cells into an amplified protective program. In the central nervous system where multiple cell types co-exist, this mechanism would allow threatened neurons to “ask for help” from glial and vascular compartments. In this review, we describe this new concept of help-me signaling, wherein damaged or diseased neurons release signals that may shift glial and vascular cells into potentially beneficial phenotypes, and help remodel the neurovascular unit. Understanding and dissecting these non-cell autonomous mechanisms of self-preservation in the CNS may lead to novel opportunities for neuroprotection and neurorecovery.

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“…Importantly, uptake of CysC occurs in cells other than the cell producing the protein (Ekstrom et al, 2008; Kolodziejczyk et al, 2010; Merz et al, 1997), suggesting that in vivo CysC can mediate important roles between cells through its uptake in target cell populations. CysC is also secreted in association with exosomes (Ghidoni et al, 2011), small lipid-membrane delineated extracellular vesicles (EVs) generated within late endosomes/multivesicular bodies (Lakkaraju and Rodriguez-Boulan, 2008; Simpson et al, 2008). Exosomes are stable vesicles, protecting their content from degradation, have the potential of transporting their content long distances within the extracellular space, and can be internalized by cells other than the cell responsible for their generation [reviewed in (Lakkaraju and Rodriguez-Boulan, 2008; Simpson et al, 2008)].…”

Section: Introductionmentioning

confidence: 99%

Cystatin C in aging and in Alzheimer’s disease

Mathews

Levy

2016

Ageing Research Reviews

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101

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Under normal conditions, the function of catalytically active proteases is regulated, in part, by their endogenous inhibitors, and any change in the synthesis and/or function of a protease or its endogenous inhibitors may result in inappropriate protease activity. Altered proteolysis as a result of an imbalance between active proteases and their endogenous inhibitors can occur during normal aging, and such changes have also been associated with multiple neuronal diseases, including Amyotrophic Lateral Sclerosis (ALS), rare heritable neurodegenerative disorders, ischemia, some forms of epilepsy, and Alzheimer’s disease (AD). One of the most extensively studied endogenous inhibitor is the cysteine-protease inhibitor cystatin C (CysC). Changes in the expression and secretion of CysC in the brain have been described in various neurological disorders and in animal models of neurodegeneration, underscoring a role for CysC in these conditions. In the brain, multiple in vitro and in vivo findings have demonstrated that CysC plays protective roles via pathways that depend upon the inhibition of endosomal-lysosomal pathway cysteine proteases, such as cathepsin B (Cat B), via the induction of cellular autophagy, via the induction of cell proliferation, or via the inhibition of amyloid-β (Aβ) aggregation. We review the data demonstrating the protective roles of CysC under conditions of neuronal challenge and the protective pathways induced by CysC under various conditions. Beyond highlighting the essential role that balanced proteolytic activity plays in supporting normal brain aging, these findings suggest that CysC is a therapeutic candidate that can potentially prevent brain damage and neurodegeneration.

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Cystatin C is released in association with exosomes: A new tool of neuronal communication which is unbalanced in Alzheimer's disease

Cited by 101 publications

References 33 publications

Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles

Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles

Help-me signaling: Non-cell autonomous mechanisms of neuroprotection and neurorecovery

Cystatin C in aging and in Alzheimer’s disease

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