Schizophrenia-Like Features in Transgenic Mice Overexpressing Human HO-1 in the Astrocytic Compartment

Song, Wei; Zukor, Hillel; Lin, Shih Hsiung; Hascalovici, Jacob R.; Liberman, Adrienne; Tavitian, Ayda; Mui, Jeannie; Vali, Hojatollah; Tong, Xin; Bhardwaj, Sanjeev K.; Srivastava, Lalit K.; Hamel, Édith; Schipper, Hyman M.

doi:10.1523/jneurosci.6469-11.2012

Cited by 59 publications

(64 citation statements)

References 83 publications

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“…HO-1 upregulation in astrocyte cells promotes intracellular oxidative stress, mitochondrial permeability transition, and mitochondrial iron deposition [23][24][25][26][27]. Recently, one study demonstrated that the overexpression of HO-1 in astrocytes of novel GFAP.HMOX1 transgenic mice results in subcortical oxidative stress, mitochondrial damage, and iron accumulation in the brain [23,28]. A study in mild cognitive impairment suggested that glial HO-1 induction is a relatively early event of sporadic AD pathogenesis, and HO-1 may play a potentially important role in AD [16,29].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Heme Oxygenase 1 Causes Cognitive Decline and Affects Pathways for Tauopathy in Mice

Wang

Yang

Peng

et al. 2014

JAD

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The stress protein heme oxygenase-1 (HO-1) is upregulated and co-localizes to pathological features, including tauopathies in the brains of individuals with Alzheimer's disease. However, the relationship between HO-1 and Alzheimer's disease remains unclear. In our previous research, the long-term overexpression of HO-1 was shown to promote tau aggregation by inducing tau phosphorylation in the mouse brain. In this study, we found that the long-term overexpression of HO-1 led to cognitive decline in transgenic mice, as determined by the water maze test, and that HO-1 can affect two pathways for tauopathy. Through one pathway, HO-1 promotes the expression of CDK5 by accumulating reactive oxygen species, which are produced by HO-1 downstream products of iron in neuro2a cell lines and mouse brain. Through the second pathway, HO-1 induces tau truncation at D421 in vivo and in vitro. Clearly, there is a HO-1-dependent mechanism responsible for tau protein phosphorylation and tau truncation in vivo and in vitro. Taken together, our results suggest that HO-1 plays an important role in the disease process of tauopathies in AD.

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Section: Introductionmentioning

confidence: 99%

Overexpression of Heme Oxygenase 1 Causes Cognitive Decline and Affects Pathways for Tauopathy in Mice

Wang

Yang

Peng

et al. 2014

JAD

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“…Conversely, chronic oxidative stress appears to increase DAT transcription (Song et al 2012 ) in certain, but not all (Kuperstein et al 2008 ), contexts.…”

Section: Oxidative Stress Effects On Dopamine Transportersmentioning

confidence: 98%

“…The prominent explanation for increased DA release in schizophrenia can be interpreted in the context of a defective corticostriatal control, most likely glutamatergic in nature, and relies on the classical distinction between tonic and phasic DA release, with a decrease of the former priming DA systems for an increase in the latter (Grace 1991(Grace , 2000. However, as exemplifi ed above, chronic ambient oxidative stress by itself could elicit increased presynaptic function comparable to that observed in schizophrenia (Song et al 2012 ).…”

Section: Increased Dopamine Releasementioning

confidence: 98%

“…HO1 overexpression induces oxidative stress. In a recent work (Song et al 2012 ), a transgenic model targeting HO1 to astrocytes (GFAP-HMOX1) has been shown to exhibit a range of behavioural abnormalities relevant to schizophrenia, notably increased locomotor activity and attenuated prepulse inhibition of the acoustic startle, a measure of sensory gating which has been shown to be disturbed in schizophrenia patients. Anatomically and histologically, the mice displayed trophic alterations of the hippocampal region, in the absence of overt neuroinfl ammation.…”

Section: Oxidative/nitrative Stress (Os) and Th Activitymentioning

confidence: 99%

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The Impact of Oxidative Stress on Dopaminergic Neurotransmission

Deslauriers

Sarret

Grignon

2014

Oxidative Stress in Applied Basic Research and Clinical Practice

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“…We then proceeded to measure HO-1 protein levels and various sterols/oxysterols (by GC-MS) in post-mortem human brain specimens ofpersons with sporadic AD, mild cognitive impairment (MCI) and no cognitive impairment (NCI) [38]. In AD and some MCIsamples, but not in NCI specimens, HO-1 levels correlated significantly with decreased total CH, increased CH precursors (together suggesting augmented CH efflux) and increased oxysterol concentrations [39], commensurate with our in vitro data. We also explored HO-1/sterol interactions in two in vivo animal models: a novel GFAP.HMOX1transgenic mouse which conditionally and selectively over-expresses the human HMOX1 gene in astrocytes [40,41]; and an established triple transgenic (3xTg-AD)mouse model of AD [42,43].…”

Section: Ho-1 As a Transducer Of Sterol Dys-regulationmentioning

confidence: 99%

HemeOxygenase-1: Transducer of Sterol Dys-Regulation in Alzheimer Disease

HM¹

2014

J Glycomics Lipidomics

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ADAD is a progressive, degenerative, dementing disorder and the sixth leading cause of the death in the US [1]. It is estimated that by the year 2050 the number of patients living with AD in the US may rise to 13-16 million while the worldwide prevalence could reach a staggering 1 in 85 or 75-100 million cases [2][3][4][5]. Pathological hallmarks of AD include extracellular deposits of β-amyloid (plaques), neurites containing hyperphosphorylated tau (neurofibrillary tangles) and loss of neurons in discrete regions of the basal forebrain, hippocampus and association cortices [6][7][8][9][10][11]. A largely overlooked pathological feature of AD, originally described over a century ago by Alois Alzheimer, is the accumulation of "adipose inclusions" or "lipoid granules" suggesting aberrant lipid homeostasis in this degenerative state [12]. Although medications (cholinesterase inhibitors) capable of conferring transient symptomatic relief are available for the management of AD, there is currently no disease-modifying intervention which unequivocally slows arrests or reverses the degenerative process. Brain Sterols/OxysterolsCholesterol (CH), its precursors and oxysterols have been consistently implicated in brain aging and neurodegeneration [2,[13][14][15]. The mechanisms underlying this relationship, however, remain ill-defined. In the CNS, sterols including CH subserves numerous biological functions essential for cell survival and homeostasis [16]. Mammalian CNS development is highly dependent on CH [17]; it is therefore not surprising that altered CH homeostasis occurs in a host of neurological conditions [18,19]. Glial CH can be enzymatically (via CH 7a-, 24-and 25-hydroxylase) or non-enzymatically (via oxidative stress) metabolized to oxysterols. On the one hand, augmented oxysterol concentrations may protect neural tissues by attenuating β-amyloiddeposition and by activation of the liver X receptor (LXR). The latter mediates up-regulation of apolipoprotein E (apoE) which, in turn, promotes glial CH efflux thatfacilitates neuronal membrane repair. However, LXR activation may also inhibit glial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and de novo CH biosynthesis. The latter establishes a negative servomechanism that limits the extent of oxysterol production and CH efflux by these cells. Moreover, primary neuronal cultures have been shown to be highly sensitive to 25-OH cytotoxicity, with lesser vulnerability to other common oxysterols such as 7-keto, 22-OH and 7β-OH [20]. Oxysterols may also promote cytotoxicity in primary astrocytes and apoptosis in microglial cells.Several critical lines of evidence have implicated sterol (dys) regulation and the formation of oxysterols in the pathogenesis of AD. For example, genetic association studies have linkedpolymorphisms ofAPOE, SORL1, CLU andABCA7 genes, which directly or indirectlyimpact lipid homeostasis, with the development of AD [21,22]. In addition, dyslipidemia has been identified in several distinct populations as an important midlife risk factor for s...

show abstract

Schizophrenia-Like Features in Transgenic Mice Overexpressing Human HO-1 in the Astrocytic Compartment

Cited by 59 publications

References 83 publications

Overexpression of Heme Oxygenase 1 Causes Cognitive Decline and Affects Pathways for Tauopathy in Mice

Overexpression of Heme Oxygenase 1 Causes Cognitive Decline and Affects Pathways for Tauopathy in Mice

The Impact of Oxidative Stress on Dopaminergic Neurotransmission

HemeOxygenase-1: Transducer of Sterol Dys-Regulation in Alzheimer Disease

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