APP Knockout Mice Experience Acute Mortality as the Result of Ischemia

Koike, Maya A.; Lin, Alexander; Pham, Jonathan; Nguyen, Elaine; Yeh, James; Rahimian, Rombod; Tromberg, Bruce J.; Choi, Bernard; Green, Kim N.; LaFerla, Frank M.

doi:10.1371/journal.pone.0042665

Cited by 40 publications

(33 citation statements)

References 36 publications

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“…For example, the AβPP gene knock out mice exhibited a slightly shorter time to vessel occlusion compared to the AβPP/KPI R13I knock in mutant mice in the carotid artery thrombosis model. This is consistent with earlier studies showing that AβPP gene knock out mice present with larger photo-induced thrombotic lesions and decreased cerebral blood flow and increased risk of mortality in response to global cerebral ischemia as compared to wild-type mice [25,52]. This supports that other regions or fragments of AβPP, such as the vasoactive Aβ peptide, can also contribute to ischemic damage.…”

Section: Discussionsupporting

confidence: 92%

Mutation of the Kunitz-type proteinase inhibitor domain in the amyloid β-protein precursor abolishes its anti-thrombotic properties in vivo

Davis

Hoos

et al. 2017

Thrombosis Research

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Introduction Kunitz proteinase inhibitor (KPI) domain-containing forms of the amyloid β-protein precursor (AβPP) inhibit cerebral thrombosis. KPI domain-lacking forms of AβPP are abundant in brain. Regions of AβPP other than the KPI domain may also be involved with regulating cerebral thrombosis. To determine the contribution of the KPI domain to the overall function of AβPP in regulating cerebral thrombosis we generated a reactive center mutant that was devoid of anti-thrombotic activity and studied its anti-thrombotic function in vitro and in vivo. Methods To determine the extent of KPI function of AβPP in regulating cerebral thrombosis we generated a recombinant reactive center KPIR13I mutant devoid of anti-thrombotic activity. The anti-proteolytic and anti-coagulant properties of wild-type and R13I mutant KPI were investigated in vitro. Cerebral thrombosis of wild-type, AβPP knock out and AβPP/KPIR13I mutant mice was evaluated in experimental models of carotid artery thrombosis and intracerebral hemorrhage. Results Recombinant mutant KPIR13I domain was ineffective in the inhibition of pro-thrombotic proteinases and did not inhibit the clotting of plasma in vitro. AβPP/KPIR13I mutant mice were similarly deficient as AβPP knock out mice in regulating cerebral thrombosis in experimental models of carotid artery thrombosis and intracerebral hemorrhage. Conclusions We demonstrate that the anti-thrombotic function of AβPP primarily resides in the KPI activity of the protein.

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Section: Discussionsupporting

confidence: 92%

Mutation of the Kunitz-type proteinase inhibitor domain in the amyloid β-protein precursor abolishes its anti-thrombotic properties in vivo

Davis

Hoos

et al. 2017

Thrombosis Research

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“…Indeed, neuropathology in AD transgenic female mice has been shown to be regulated by both estrogen and progesterone. Nevertheless, a substantial APP loss would be detrimental, because this protein has endogenous roles important in synaptic function (Koike et al, 2012; Muller and Zheng 2012). Therefore, therapeutic strategies will require caution regarding reductions in endogenous APP.…”

Section: Resultsmentioning

confidence: 99%

A comparative evaluation of treatments with 17β-estradiol and its brain-selective prodrug in a double-transgenic mouse model of Alzheimer's disease

Tschiffely

Schuh

Prókai-Tátrai

et al. 2016

Hormones and Behavior

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Estrogens are neuroprotective and, thus, potentially useful for the therapy of Alzheimer’s disease; however, clinical use of hormone therapy remains controversial due to adverse peripheral effects. The goal of this study was to investigate the benefits of treatment with 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), a brain-selective prodrug of 17β-estradiol, in comparison with the parent hormone using APPswe/PS1dE9 double transgenic mice to model the pathology of the disease. Ovariectomized and intact females were continuously treated with vehicle, 17β-estradiol, or DHED via subcutaneous osmotic pumps from 6 to 8 months of age. We confirmed that this prolonged treatment with DHED did not stimulate uterine tissue, whereas 17β-estradiol treatment increased uterine weight. Amyloid precursor protein decreased in both treatment groups of intact, but not in ovariectomized double transgenic females in which ovariectomy already decreased the expression of this protein significantly. However, reduced brain amyloid-β peptide levels could be observed for both treatments. Consequently, double-transgenic ovariectomized and intact mice had higher cognitive performance compared to untreated control animals in response to both estradiol and DHED administrations. Overall, the tested brain-selective 17β-estradiol prodrug proved to be an effective early-stage intervention in an Alzheimer’s disease-relevant mouse model without showing systemic impact and, thus, warrants further evaluation as a potential therapeutic candidate.

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“…However, APP knockout mice are highly susceptible to cerebral ischemia (Koike et al . ), indicating that APP and its fragments have important roles in the response to hypoxia. Robinson et al .…”

Section: Is Ad Pathology a Byproduct Of Hypoxia‐induced Rescue Procesmentioning

confidence: 99%

Hypoxia/ischemia activate processing of Amyloid Precursor Protein: impact of vascular dysfunction in the pathogenesis of Alzheimer's disease

Salminen

Kauppinen

Kaarniranta

2017

Journal of Neurochemistry

170

124

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Alzheimer's disease (AD) is associated with deficiencies in cerebrovascular functions, e.g. reduced cerebral blood flow and capillary amyloid angiopathy, both of which are evident during the early phase of AD, thus local hypoxia/ischemia could augment the pathogenesis of AD. There is abundant literature revealing that exposures to hypoxia/ischemia increase the amyloidogenic processing of amyloid-b precursor protein (APP) leading to the accumulation of amyloid-b peptides in brain. This hypoxia-induced response has been attributed to a significant increase in the activities of b-and csecretases, whereas a-secretase activity decreases in hypoxia. Recent studies have indicated that hypoxia-inducible factor-1a (HIF-1a) stimulates the transcription of the bsecretase 1 (BACE1) gene through the hypoxia-response element in the BACE1 promoter. Moreover, HIF-1a protein can directly interact with the c-secretase complex and increase its activity in a non-transcriptional manner. Hypoxia/ischemia also trigger endoplasmic reticulum stress and impair autophagy in brain, which consequently can stimulate the expression of presenilin 1 (PS1) and activate c-secretase. Subsequently, PS1 protein can stabilize HIF-1a protein and in addition, APP intracellular domain peptide is able to induce the expression of HIF-1a. The activation of b-and c-secretases is an evolutionarily conserved hypoxia response, e.g. it is also present in zebrafish. Given that b-and c-secretases have many substrates in addition to APP, one could postulate that AD pathology is a byproduct of the rescue process mediated by these two aspartyl proteinases under hypoxic/ischemic conditions. We will review the recent evidence indicating that vascular dysfunctions can provoke AD pathology by activating b-and c-secretases.

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APP Knockout Mice Experience Acute Mortality as the Result of Ischemia

Cited by 40 publications

References 36 publications

Mutation of the Kunitz-type proteinase inhibitor domain in the amyloid β-protein precursor abolishes its anti-thrombotic properties in vivo

Mutation of the Kunitz-type proteinase inhibitor domain in the amyloid β-protein precursor abolishes its anti-thrombotic properties in vivo

A comparative evaluation of treatments with 17β-estradiol and its brain-selective prodrug in a double-transgenic mouse model of Alzheimer's disease

Hypoxia/ischemia activate processing of Amyloid Precursor Protein: impact of vascular dysfunction in the pathogenesis of Alzheimer's disease

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