Myelin proteins in aging human brain

Wender, M; Adamczewska-Goncerzewicz, Z; Dorszewska, Jolanta

doi:10.1007/bf03160993

Cited by 10 publications

(8 citation statements)

References 12 publications

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“…We then elucidated the nature of the soluble signal by factor removal experiments using mass spectrometry lipidomics to identify that the lipid was lysophosphatidylcholine (LPC). Our findings have been supported by previous studies where, increased LPC levels have been observed in multiple sclerosis and in aged human brain (Andreoli et al, 1973;Wender et al, 1988). However, the precise mechanism behind LPC production has not been fully elucidated.…”

Section: Discussionsupporting

confidence: 91%

Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration

Sundaram¹,

Chan²,

Poore³

et al. 2012

J. Neurosci.

113

100

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The deregulation of cyclin-dependent kinase 5 (Cdk5) by p25 has been shown to contribute to the pathogenesis in a number of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD). In particular, p25/Cdk5 has been shown to produce hyperphosphorylated tau, neurofibrillary tangles as well as aberrant amyloid precursor protein processing found in AD. Neuroinflammation has been observed alongside the pathogenic process in these neurodegenerative diseases, however the precise mechanism behind the induction of neuroinflammation and the significance in the AD pathogenesis has not been fully elucidated. In this report, we uncover a novel pathway for p25-induced neuroinflammation where p25 expression induces an early trigger of neuroinflammation in vivo in mice. Lipidomic mass spectrometry, in vitro coculture and conditioned media transfer experiments show that the soluble lipid mediator lysophosphatidylcholine (LPC) is released by p25 overexpressing neurons to initiate astrogliosis, neuroinflammation and subsequent neurodegeneration. Reverse transcriptase PCR and gene silencing experiments show that cytosolic phospholipase 2 (cPLA2) is the key enzyme mediating the p25-induced LPC production and cPLA2 upregulation is critical in triggering the p25-mediated inflammatory and neurodegenerative process. Together, our findings delineate a potential therapeutic target for the reduction of neuroinflammation in neurodegenerative diseases including AD.

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Section: Discussionsupporting

confidence: 91%

Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration

Sundaram¹,

Chan²,

Poore³

et al. 2012

J. Neurosci.

113

100

View full text Add to dashboard Cite

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“…Is there any relationship between the age‐related change of white matter and age‐related change of the capillaries in white matter? Wender et al (1991) investigated white matter of temporal, parietal and occipital lobes of 13 subjects using histological methods and biochemical techniques. They found that there were significantly age‐related change of the expression of myelin‐associated protein in both the brains with vascular changes only and brains with senile atrophy of the Alzheimer type.…”

Section: Discussionmentioning

confidence: 99%

Stereological Investigation of Age‐Related Changes of the Capillaries in White Matter

Shao

Chen

et al. 2010

The Anatomical Record

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We, for the first time, investigated the age-related changes of the capillaries in white matter using immunohistochemistry and stereological techniques. Ten young female (7 months) and 10 aged female (27 months) rats were used. The total length, total volume, and total surface area of the capillaries in white matter of aged rats were all significantly lower than those of young rats. The age-related changes of the capillaries in white matter may have important implications for age-related white matter atrophy and age-related cognitive impairments.

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“…Elevated levels of LPC have been reported in a number of neurological conditions with neuroinflammation as a putative pathological component. Examples include increased LPC in plasma of multiple sclerosis patients (Andreoli et al, 1973) and in white matter of aged human brain exhibiting senile atrophy of Alzheimer type (Wender et al, 1988). LPC levels have been reported to be significantly increased in a rat model of cerebral ischemia (Kinouchi et al, 1990).…”

Section: Introductionmentioning

confidence: 98%

Lysophosphatidylcholine induces glial cell activation: Role of rho kinase

Sheikh

Nagai

Ryu

et al. 2008

Glia

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Lysophosphatidylcholine (LPC), a major phospholipid component of atherogenic oxidized LDL, is implicated in atherosclerosis and, recently, in neurodegenerative diseases. We investigated the immunomodulatory functions of LPC in the central nervous system (CNS) using both an in vivo rat model, and in vitro culture systems of human primary astrocytes and a microglia cell line, HMO6. Compared with PBS injection, 20 nmol LPC-injection into the rat striatum increased astrocyte and microglial accumulation and elevated iNOS expression; concomitantly a time-dependent decrease in number of neurons was exhibited. In vitro studies on astrocytes and HMO6 cells showed that LPC increased the gene expression of proinflammatory factors IL-1beta, COX-2, and GM-CSF. LPC also induced chemotactic responses in HMO6 cells. Inhibition of rho kinase by fasudil, Y27632, or expressing a dominant negative form of rho kinase inhibited the LPC-induced IL-1beta mRNA expression in both astrocytes and HMO6. Moreover, intraperitoneal fasudil injection inhibited the LPC-induced microglial accumulation and iNOS expression and also was effective in protecting against neuronal loss. Silencing G2A, a specific receptor for LPC, inhibited proinflammatory gene expression and HMO6 migration. Overall, our results indicate that LPC induced considerable neuroinflammatory reactivity in glia mediated by rho kinase-dependent pathways with inhibition of these pathways conferring significant extents of neuroprotection.

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Myelin proteins in aging human brain

Cited by 10 publications

References 12 publications

Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration

Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration

Stereological Investigation of Age‐Related Changes of the Capillaries in White Matter

Lysophosphatidylcholine induces glial cell activation: Role of rho kinase

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