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Aberrant expression of myeloperoxidase in astrocytes promotes phospholipid oxidation and memory deficits in a mouse model of Alzheimer disease.

ABSTRACT: Myeloperoxidase (MPO) is expressed in Alzheimer disease (AD) but not normal aged brain. A functional -463G/A MPO promoter polymorphism has been associated with AD risk through as yet unidentified mechanisms. Here we report that human MPO-463G allele, but not MPO-463A or mouse MPO, is strongly expressed in astrocytes and deposited in plaques in huMPO transgenic mice crossed to the APP23 model. MPO is similarly expressed in astrocytes in human AD tissue. In cortical homogenates of the MPOG-APP23 model, MPO expression correlated with increased levels of a lipid peroxidation product, 4-hydroxynonenal. Fluorescence high-performance liquid chromatography and electrospray ionization mass spectroscopy identified selective accumulation of phospholipid hydroperoxides in two classes of anionic phospholipids, phosphatidylserine (PS-OOH) and phosphatidylinositol (PI-OOH). The same molecular species of PS-OOH and PI-OOH were elevated in human AD brains as compared with non-demented controls. Augmented lipid peroxidation in MPOG-APP23 mice correlated with greater memory deficits. We suggest that aberrant huMPO expression in astrocytes leads to a specific pattern of phospholipid peroxidation and neuronal dysfunction contributing to AD.

SUBMITTER: Maki RA

PROVIDER: S-EPMC2631957 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Aberrant expression of myeloperoxidase in astrocytes promotes phospholipid oxidation and memory deficits in a mouse model of Alzheimer disease.

Maki Richard A RA Tyurin Vladimir A VA Lyon Robert C RC Hamilton Ronald L RL DeKosky Steven T ST Kagan Valerian E VE Reynolds Wanda F WF

The Journal of biological chemistry 20081205 5

Myeloperoxidase (MPO) is expressed in Alzheimer disease (AD) but not normal aged brain. A functional -463G/A MPO promoter polymorphism has been associated with AD risk through as yet unidentified mechanisms. Here we report that human MPO-463G allele, but not MPO-463A or mouse MPO, is strongly expressed in astrocytes and deposited in plaques in huMPO transgenic mice crossed to the APP23 model. MPO is similarly expressed in astrocytes in human AD tissue. In cortical homogenates of the MPOG-APP23 m ...[more]

PMID: 19059911

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Project description:BackgroundRecently, we and other researchers reported that brain metabolic disorders are implicated in Alzheimer's disease (AD), a progressive, devastating and incurable neurodegenerative disease. Hence, novel therapeutic approaches are urgently needed to explore potential and novel therapeutic targets/agents for the treatment of AD. The neuronal adiponectin receptor 1 (AdipoR1) is an emerging potential target for intervention in metabolic-associated AD. We aimed to validate this hypothesis and explore in-depth the therapeutic effects of an osmotin-derived adiponectin-mimetic novel nonapeptide (Os-pep) on metabolic-associated AD.MethodsWe used an Os-pep dosage regimen (5 μg/g, i.p., on alternating days for 45 days) for APP/PS1 in amyloid β oligomer-injected, transgenic adiponectin knockout (Adipo-/-) and AdipoR1 knockdown mice. After behavioral studies, brain tissues were subjected to biochemical and immunohistochemical analyses. In separate cohorts of mice, electrophysiolocal and Golgi staining experiments were performed. To validate the in vivo studies, we used human APP Swedish (swe)/Indiana (ind)-overexpressing neuroblastoma SH-SY5Y cells, which were subjected to knockdown of AdipoR1 and APMK with siRNAs, treated with Os-pep and other conditions as per the mechanistic approach, and we proceeded to perform further biochemical analyses.ResultsOur in vitro and in vivo results show that Os-pep has good safety and neuroprotection profiles and crosses the blood-brain barrier. We found reduced levels of neuronal AdipoR1 in human AD brain tissue. Os-pep stimulates AdipoR1 and its downstream target, AMP-activated protein kinase (AMPK) signaling, in AD and Adipo-/- mice. Mechanistically, in all of the in vivo and in vitro studies, Os-pep rescued aberrant neuronal metabolism by reducing neuronal insulin resistance and activated downstream insulin signaling through regulation of AdipoR1/AMPK signaling to consequently improve the memory functions of the AD and Adipo-/- mice, which was associated with improved synaptic function and long-term potentiation via an AdipoR1-dependent mechanism.ConclusionOur findings show that Os-pep activates AdipoR1/AMPK signaling and regulates neuronal insulin resistance and insulin signaling, which subsequently rescues memory deficits in AD and adiponectin-deficient models. Taken together, the results indicate that Os-pep, as an adiponectin-mimetic novel nonapeptide, is a valuable and promising potential therapeutic candidate to treat aberrant brain metabolism associated with AD and other neurodegenerative diseases.

Project description:Microtubule-associated protein tau aggregates constitute the characteristic neuropathological features of several neurodegenerative diseases grouped under the name of tauopathies. It is now clear that the process of tau aggregation is associated with neurodegeneration. Several transgenic tau mouse models have been developed where tau progressively aggregates, causing neuronal death. Previously we have shown that transplantation of astrocytes in P301S tau transgenic mice rescues cortical neuron death, implying that the endogenous astrocytes are deficient in survival support. We now show that the gliosis markers Glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100β) are elevated in brains from P301S tau mice compared to control C57Bl/6 mice whereas the expression of proteins involved in glutamine/glutamate metabolism are reduced, pointing to a functional deficit. To test whether astrocytes from P301S mice are intrinsically deficient, we co-cultured astrocytes and neurons from control and P301S mice. Significantly more C57-derived and P301S-derived neurons survived when cells were cultured with C57-derived astrocytes or astrocyte conditioned medium (C57ACM) than with P301S-derived astrocytes or astrocyte conditioned medium (P301SACM), or ACM from P301L tau mice, where the transgene is also specifically expressed in neurons. The astrocytic alterations developed in mice during the first postnatal week of life. In addition, P301SACM significantly decreased presynaptic (synaptophysin, SNP) and postsynaptic (postsynaptic density protein 95, PSD95) protein expression in cortical neuron cultures whereas C57ACM enhanced these markers. Since thrombospondin 1 (TSP-1) is a major survival and synaptogenic factor, we examined whether TSP-1 is deficient in P301S mouse brains and ACM. Significantly less TSP-1 was expressed in the brains of P301S tau mice or produced by P301S-derived astrocytes, whereas supplementation of P301SACM with TSP-1 increased its neurosupportive capacity. Our results demonstrate that P301S-derived astrocytes acquire an early functional deficiency that may explain in part the loss of cortical neurons in the P301S tau mice.

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Aberrant expression of myeloperoxidase in astrocytes promotes phospholipid oxidation and memory deficits in a mouse model of Alzheimer disease.

Publications

Aberrant expression of myeloperoxidase in astrocytes promotes phospholipid oxidation and memory deficits in a mouse model of Alzheimer disease.

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