APP/PS1 mice overexpressing SREBP-2 exhibit combined Aβ accumulation and tau pathology underlying Alzheimer's disease

May 8, 2013Human molecular genetics

Mice with extra SREBP-2 show combined buildup of harmful proteins linked to Alzheimer's disease

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Abstract

APP/PS1/SREBP-2 mice exhibited early mitochondrial cholesterol loading and mGSH depletion.

Excess brain cholesterol may regulate amyloid-β (Aβ) deposition, impacting cholesterol homeostasis.
Mitochondrial glutathione (mGSH) depletion is associated with increased Aβ neurotoxicity.
Accelerated β-secretase activation and Aβ accumulation were observed in APP/PS1/SREBP-2 mice compared to APP/PS1 mice.
Increased synaptotoxicity and neuronal death in APP/PS1/SREBP-2 mice resulted in early memory impairment.
Tau pathology in APP/PS1/SREBP-2 mice included increased tau hyperphosphorylation and neurofibrillary tangle formation.
Restoration of mGSH levels in APP/PS1/SREBP-2 mice partially prevented tau kinase activation and reduced Aβ deposition.

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Current evidence indicates that excess brain cholesterol regulates amyloid-β (Aβ) deposition, which in turn can regulate cholesterol homeostasis. Moreover, Aβ neurotoxicity is potentiated, in part, by mitochondrial glutathione (mGSH) depletion. To better understand the relationship between alterations in cholesterol homeostasis and Alzheimer's disease (AD), we generated a triple transgenic mice featuring sterol regulatory element-binding protein-2 (SREBP-2) overexpression in combination with APPswe/PS1ΔE9 mutations (APP/PS1) to examine key biochemical and functional characteristics of AD. Unlike APP/PS1 mice, APP/PS1/SREBP-2 mice exhibited early mitochondrial cholesterol loading and mGSH depletion. Moreover, β-secretase activation and Aβ accumulation, correlating with oxidative damage and neuroinflammation, were accelerated in APP/PS1/SREBP-2 mice compared with APP/PS1 mice. Triple transgenic mice displayed increased synaptotoxicity reflected by loss of synaptophysin and neuronal death, resulting in early object-recognition memory impairment associated with deficits in spatial memory. Interestingly, tau pathology was present in APP/PS1/SREBP-2 mice, manifested by increased tau hyperphosphorylation and cleavage, activation of tau kinases and neurofibrillary tangle (NFT) formation without expression of mutated tau. Importantly, in vivo treatment with the cell permeable GSH ethyl ester, which restored mGSH levels in APP/PS1/SREBP-2 mice, partially prevented the activation of tau kinases, reduced abnormal tau aggregation and Aβ deposition, resulting in attenuated synaptic degeneration. Taken together, these results show that cholesterol-mediated mGSH depletion is a key event in AD progression, accelerating the onset of key neuropathological hallmarks of the disease. Thus, therapeutic approaches to recover mGSH may represent a relevant strategy in the treatment of AD.

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APP/PS1 mice overexpressing SREBP-2 exhibit combined Aβ accumulation and tau pathology underlying Alzheimer's disease

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