Myeloid microvesicles in cerebrospinal fluid are associated with myelin damage and neuronal loss in mild cognitive impairment and <scp>A</scp>lzheimer disease

Agosta, Federica; Libera, Dacia Dalla; Spinelli, Edoardo Gioele; Finardi, Annamaria; Canu, Elisa; Bergami, Alessandra; Bocchio-Chiavetto, Luisella; Baronio, Manuela; Comi, Giancarlo; Martino, Gianvito; Matteoli, Michela; Magnani, Giuseppe; Verderio, Claudia; Furlan, Roberto

doi:10.1002/ana.24235

Cited by 96 publications

(84 citation statements)

References 61 publications

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“…Some are components of the innate immune system and Finally, reactive microglia release MVs and exosomes, which may have a dual role in motor neuron degeneration (Figure 3). On the one hand, MVs released by reactive microglia carry pro-inflammatory cytokines [221] and induce an inflammatory reaction in target cells [222]. Microglia-derived MVs also promote precipitation of misfolded proteins in Parkinson's and Alzheimer's disease models [223,224].…”

Section: Microglia May Drive Als Pathophysiologymentioning

confidence: 99%

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

Rodrı́guez¹,

Mahy²

2016

CMC

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Section: Microglia May Drive Als Pathophysiologymentioning

confidence: 99%

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

Rodrı́guez¹,

Mahy²

2016

CMC

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“…The release of aggregates might result from synapse degeneration or from an exocytic process, or it could be part of normal synaptic physiology [21]. Finally, pathology progression in AD along WM tracts might be driven by neuroinflammation [71]. A recent study found that higher levels of myeloid microvesicles in the cerebrospinal fluid correlated with WM tract damage in MCI and with hippocampal atrophy in AD [71].…”

Section: Neuroimaging Studiesmentioning

confidence: 99%

“…Finally, pathology progression in AD along WM tracts might be driven by neuroinflammation [71]. A recent study found that higher levels of myeloid microvesicles in the cerebrospinal fluid correlated with WM tract damage in MCI and with hippocampal atrophy in AD [71]. According to the model proposed in this study, hippocampal microglia activation, in the presence of Aβ accumulation, produces neurotoxic and oligodendrotoxic oligomers that, through WM tract damage, spread disease to neighboring and connected areas, causing local microglia activation and propagation of disease through the same sequence of events [71].…”

Section: Neuroimaging Studiesmentioning

confidence: 99%

“…The damage caused on both neurons and oligodendrocytes by microvesicles results in degeneration of projecting fibers from the initially involved to more distal areas (3b), causing the diffusion of the pathogenic process to new brain regions (4). Reproduced with permission from Alves et al [69] (panels a and b ), from Frost and Diamond [21] (panel c ) and from Agosta et al [71] (panel d ). …”

Section: Introductionmentioning

confidence: 99%

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Insights into White Matter Damage in Alzheimer's Disease: From Postmortem to in vivo Diffusion Tensor MRI Studies

Caso¹,

Filippi²

2015

Neurodegener Dis

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Background: Alzheimer's disease (AD) has traditionally been considered a disease of the gray matter (GM). However, several pathological and neuroimaging studies provided evidence of white matter (WM) abnormalities in this disease. The advent of diffusion tensor (DT) MRI allowed researchers to study in vivo cerebral WM abnormalities in AD, including the earliest stage of the disease and its atypical variants. Objective: To provide a concise overview of the main neuropathological and DT MRI studies that explored WM damage in AD providing new insights into the underlying pathophysiological mechanisms. Results: Neuropathological studies revealed that GM and WM changes did not concur regionally in many areas, where well-preserved GM often lay over severely changed WM also in nondemented subjects with an underlying AD pathology. DT MRI studies confirmed in vivo a severe WM involvement in classical and atypical AD variants and in the prodromal stage of the disease. Microstructural WM damage was severer and more distributed than expected on the basis of cortical atrophy in all clinical AD phenotypes. Conclusions: AD is characterized by a relevant involvement of the WM as demonstrated by postmortem and in vivo evidence. WM microstructural damage in AD is not always secondary to neuronal loss, suggesting a role of other pathological mechanisms such as prion-like propagation of altered proteins or neuroinflammation. DT MRI offers new insight into AD pathophysiology and, more importantly, new possible targets for future experimental therapies.

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“…EVs are increasingly being associated with neurodegenerative disease progression and pathologies [96][97][98][99]. In the CNS, EVs have been shown to be produced by several cell types including neurones, microglia, oligodendrocytes, astrocytes and embryonic neural stem cells [9] and play important roles in the development and function of the nervous system [100].…”

Section: Evs In Neurodegenerative Diseasesmentioning

confidence: 99%

Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

Lange¹,

Kholia²,

Kosgodage³

et al. 2017

Preprint

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Extracellular vesicle (EV) release, which occurs in most eukaryotic cells, has recently been associated with peptidylarginine deiminase (PAD)-driven protein deimination. Evidence points to the involvement of deiminated cytoskeletal proteins and changes in histone deimination. Both PADs and EVs are associated with various pathologies including cancers, autoimmune and neurodegenerative diseases. The elevated PAD expression observed in cancers may contribute to increase in EV shedding observed from cancer cells, contributing to cancer progression. Similarly, elevated PAD expression observed in neurodegenerative diseases may cause increased EV shedding and spread of neurodegenerative EV cargo, contributing to disease progression and pathologies. Pharmacological inhibition of PAD-mediated deimination using pan-PAD inhibitor Cl-amidine, reduced cellular EV release in prostate cancer cells, rendering them significantly more susceptible to chemotherapeutic drugs. Studies on models of central nervous system damage have demonstrated critical functional roles for PADs and neuroprotective effects using PAD inhibitors in vivo, while human neurodegenerative iPSC in vitro models showed evidence of increased protein deimination. Besides using refined PAD inhibitors to selectively manipulate EV biogenesis for novel combination therapies in cancer treatment, we also speculate how EV biogenesis could be targeted via the newly identified PAD-pathway to ameliorate neurodegenerative disease progression.

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Myeloid microvesicles in cerebrospinal fluid are associated with myelin damage and neuronal loss in mild cognitive impairment and Alzheimer disease

Cited by 96 publications

References 61 publications

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

Insights into White Matter Damage in Alzheimer's Disease: From Postmortem to in vivo Diffusion Tensor MRI Studies

Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

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