Neurodegeneration and cognitive impairment in apoE-deficient mice is ameliorated by infusion of recombinant apoE

Masliah, Eliezer; Samuel, William; Veinbergs, Isaac; Mallory, Margaret; Mante, Michael; Saitoh, Tsunao

doi:10.1016/s0006-8993(96)01420-5

Cited by 134 publications

(98 citation statements)

References 26 publications

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“…These findings suggest that the availability of apoE is a key factor in protecting the brain after ischaemic brain injury. This is supported by reports showing neuroprotection after restoration of apoE levels in APOE deficient mice by administration of exogenous apoE (Masliah et al, 1997;Horsburgh et al, 2000b) or by intrathecal delivery of an apoE-derived peptide in rat pups after perinatal hypoxic-ischaemic injury (McAdoo et al, 2005). Collectively, these data indicate that augmenting endogenous apoE levels in the brain could improve outcome after cerebral ischaemia.…”

Section: Introductionsupporting

confidence: 67%

APOE ε3 Gene Transfer Attenuates Brain Damage after Experimental Stroke

McColl

McGregor

Wong

et al. 2006

J Cereb Blood Flow Metab

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Apolipoprotein E (apoE, protein; APOE, gene) is the major lipid-transport protein in the brain and plays an important role in modulating the outcome and regenerative processes after acute brain injury. The aim of the present study was to determine if gene transfer of the e3 form of APOE improves outcome in a murine model of transient focal cerebral ischaemia. Mice received an intrastriatal injection of vehicle, a second-generation adenoviral vector containing the green fluorescent protein gene (Ad-GFP) or a vector containing the APOE e3 gene (Ad-APOE) 3 days before 60 mins focal ischaemia. Green fluorescent protein expression was observed in cells throughout the striatum and subcortical white matter indicating successful gene transfer and expression. ApoE levels in the brain were significantly increased after Ad-APOE compared with Ad-GFP or vehicle treatment. Ad-APOE treatment reduced the volume of ischaemic damage by 50% compared with Ad-GFP or vehicle treatment (1363 versus 2964 versus 2765 mm 3 ). The extent of postischaemic apoE immunoreactivity was enhanced in Ad-APOE compared with Ad-GFP or vehicle treated mice. These results show the ability of APOE gene transfer to markedly improve outcome after cerebral ischaemia and suggest that modulating apoE levels may be a potential strategy in human stroke therapy.

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Section: Introductionsupporting

confidence: 67%

APOE ε3 Gene Transfer Attenuates Brain Damage after Experimental Stroke

McColl

McGregor

Wong

et al. 2006

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…Apoe Ϫ/Ϫ mice have been the subject of numerous behavioral investigations (for example, see Gordon et al, 1995;Masliah et al, 1997;Oitzl et al, 1997;Anderson et al, 1998;Fisher et al, 1998;Raber et al, 1998). The findings of the current study underline the need to carefully consider the altered HPA axis and increased anxiety of these mice in the interpretation of behavioral alterations identified in these animals.…”

Section: Discussionmentioning

confidence: 76%

Hypothalamic–Pituitary–Adrenal Dysfunction inApoe^−/−Mice: Possible Role in Behavioral and Metabolic Alterations

et al. 2000

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Several neurological diseases are frequently accompanied by dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis regulates the secretion of glucocorticoids (GCs), which play important roles in diverse brain functions, including cognition, emotion, and feeding. Under physiological conditions, GCs are adaptive and beneficial; however, prolonged elevations in GC levels may contribute to neurodegeneration and brain dysfunction. In the current study, we demonstrate that apolipoprotein E (apoE) deficiency results in agedependent dysregulation of the HPA axis through a mechanism affecting primarily the adrenal gland. Apoe Ϫ/Ϫ mice, which develop neurodegenerative alterations as they age, had an age-dependent increase in basal adrenal corticosterone content and abnormally increased plasma corticosterone levels after restraint stress, whereas their plasma and pituitary adrenocorticotropin levels were either unchanged or lower than those in controls. HPA axis dysregulation was associated with behavioral and metabolic alterations. When anxiety levels were assessed in the elevated plus maze, Apoe Ϫ/Ϫ mice showed more anxiety than wild-type controls. Apoe Ϫ/Ϫ mice also showed reduced activity in the open field. Finally, Apoe Ϫ/Ϫ mice showed age-dependent increases in food and water intake, stomach and body weights, and decreases in brown and white adipose tissues. These results support a key role for apoE in the tonic inhibition of steroidogenesis and HPA axis activity and have important implications for the behavioral analysis of Apoe Ϫ/Ϫ mice.

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“…Accompanying the neurodegenerative effects of the ApoE knockout are behavioral deficits that can be rescued by infusing recombinant ApoE. 103,104 These results support a role for ApoE in neuroprotection. Evidence also exists for the involvement of ApoE in both A␤ fibrillization and clearance.…”

Section: Interactions Of Presenilins and Appmentioning

confidence: 78%

Transgenic models of Alzheimer’s disease: Learning from animals

2005

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Summary:As the scope of the problem of Alzheimer's disease (AD) grows due to an aging population, research into the devastating condition has taken on added urgency. Rare inherited forms of AD provide insight into the molecular pathways leading to degeneration and have made possible the development of transgenic animal models. Several of these models are based on the overexpression of amyloid precursor protein (APP), presenilins, or tau to cause production and accumulation of amyloid-␤ into plaques or hyperphosphorylated tau into neurofibrillary tangles. Producing these characteristic neuropathological lesions in animals causes progressive neurodegeneration and in some cases similar behavioral disruptions to those seen in AD patients. Knockout models of proteins involved in AD have also been generated to explore the native functions of these genes and examine whether pathogenesis is due to loss of function or toxic gain of function in these systems. Although none of the transgenic lines models the human condition exactly, the ability to study similar pathological processes in living animals have provided numerous insights into disease mechanisms and opportunities to test therapeutic agents. This chapter reviews animal models of AD and their contributions to developing therapeutic approaches for AD.

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Neurodegeneration and cognitive impairment in apoE-deficient mice is ameliorated by infusion of recombinant apoE

Cited by 134 publications

References 26 publications

APOE ε3 Gene Transfer Attenuates Brain Damage after Experimental Stroke

APOE ε3 Gene Transfer Attenuates Brain Damage after Experimental Stroke

Hypothalamic–Pituitary–Adrenal Dysfunction inApoe^−/−Mice: Possible Role in Behavioral and Metabolic Alterations

Transgenic models of Alzheimer’s disease: Learning from animals

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Neurodegeneration and cognitive impairment in apoE-deficient mice is ameliorated by infusion of recombinant apoE

Cited by 134 publications

References 26 publications

APOE ε3 Gene Transfer Attenuates Brain Damage after Experimental Stroke

APOE ε3 Gene Transfer Attenuates Brain Damage after Experimental Stroke

Hypothalamic–Pituitary–Adrenal Dysfunction inApoe−/−Mice: Possible Role in Behavioral and Metabolic Alterations

Transgenic models of Alzheimer’s disease: Learning from animals

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Hypothalamic–Pituitary–Adrenal Dysfunction inApoe^−/−Mice: Possible Role in Behavioral and Metabolic Alterations