BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice

Ohno, Minoru; Cole, Sarah L.; Yasvoina, Marina V.; Zhao, Jie; Citron, Martin; Berry, Robert W.; Disterhoft, John F.; Vassar, Robert

doi:10.1016/j.nbd.2006.12.008

Cited by 267 publications

(244 citation statements)

References 77 publications

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“…For example, 5XFAD mice exhibit neuron loss and memory deficits that are associated with amyloid pathology (Oakley et al , 2006). Importantly, BACE1 knockout abolishes Aβ deposition in 5XFAD mice and at the same time prevents both memory deficits and neuron loss in this and other mouse models (Ohno et al , 2007). Thus, cerebral Aβ accumulation is responsible for neuron loss and memory deficits in these lines, rather than transgene overexpression, although effects of β‐CTF overexpression cannot be ruled out.…”

Section: Studies On First‐generation Mouse Modelsmentioning

confidence: 68%

APP mouse models for Alzheimer's disease preclinical studies

et al. 2017

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Animal models of human diseases that accurately recapitulate clinical pathology are indispensable for understanding molecular mechanisms and advancing preclinical studies. The Alzheimer's disease (AD) research community has historically used first‐generation transgenic (Tg) mouse models that overexpress proteins linked to familial AD (FAD), mutant amyloid precursor protein (APP), or APP and presenilin (PS). These mice exhibit AD pathology, but the overexpression paradigm may cause additional phenotypes unrelated to AD. Second‐generation mouse models contain humanized sequences and clinical mutations in the endogenous mouse App gene. These mice show Aβ accumulation without phenotypes related to overexpression but are not yet a clinical recapitulation of human AD. In this review, we evaluate different APP mouse models of AD, and review recent studies using the second‐generation mice. We advise AD researchers to consider the comparative strengths and limitations of each model against the scientific and therapeutic goal of a prospective preclinical study.

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Section: Studies On First‐generation Mouse Modelsmentioning

confidence: 68%

APP mouse models for Alzheimer's disease preclinical studies

et al. 2017

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“…First, it is possible that pharmacological approaches with the potent agonist 7,8-DHF may activate BDNF-TrkB signaling more efficiently than gene delivery or stem cell strategies. Furthermore, previous studies from our laboratory and others have demonstrated that elevations in BACE1 have an important role in accelerating disease progression in 5XFAD mouse brains (Devi and Ohno, 2010b;O'Connor et al, 2008;Ohno et al, 2007;Zhang et al, 2009;Zhao et al, 2007) as well as in sporadic AD brains (Fukumoto et al, 2002;Li et al, 2004;Yang et al, 2003).…”

Section: Discussionmentioning

confidence: 82%

“…Previous studies from our laboratory and others have demonstrated that 5XFAD mice recapitulate significant elevations in BACE1 expression (Devi and Ohno, 2010b;Ohno et al, 2007;Zhang et al, 2009;Zhao et al, 2007) reminiscent of sporadic AD brains (Fukumoto et al, 2002;Li et al, 2004;Yang et al, 2003). A two-way ANOVA for BACE1 protein levels revealed significant main effects of genotype (F(1, 24) ¼ 66.38, po0.05) and drug (F(1, 24) ¼ 30.69, po0.05), but not a significant genotype Â drug interaction (Figure 5b).…”

Section: Systemic 78-dhf Reduces Bace1 and B-amyloidogenesis In 5xfamentioning

confidence: 88%

“…These behavioral deficits are observed concomitant with the onset of hippocampal CA1 synaptic dysfunctions such as reduced basal transmission and long-term potentiation (LTP: a synaptic plasticity model for learning and memory) (Kimura and Ohno, 2009). Furthermore, 5XFAD mice begin to exhibit elevations in expression levels of the b-secretase (b-site APP cleaving enzyme 1: BACE1), which is responsible for initiating the production of Ab, at 6-9 months of age (Devi and Ohno, 2010b;Ohno et al, 2007;Zhang et al, 2009;Zhao et al, 2007), as observed in sporadic AD brains (Fukumoto et al, 2002;Li et al, 2004;Yang et al, 2003). To rigorously test the therapeutic potential of 7,8-DHF, we used the advanced stage of 5XFAD transgenic mice (12-15 months of age) that is more relevant to clinic AD cases manifesting robust amyloidosis, BACE1 elevations, BDNF-TrkB dysfunction, and profound memory impairments.…”

Section: Introductionmentioning

confidence: 99%

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7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease

Devi

Ohno

2011

Neuropsychopharmacol

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Increasing evidence suggests that reductions in brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) may have a role in the pathogenesis of Alzheimer's disease (AD). However, the efficacy and safety profile of BDNF therapy (eg, gene delivery) remains to be established toward clinical trials. Here, we evaluated the effects of 7,8-dihydroxyflavone (7,8-DHF), a recently identified small-molecule TrkB agonist that can pass the blood-brain barrier, in the 5XFAD transgenic mouse model of AD. 5XFAD mice at 12-15 months of age and non-transgenic littermate controls received systemic administration of 7,8-DHF (5 mg/kg, i.p.) once daily for 10 consecutive days. We found that 7,8-DHF rescued memory deficits of 5XFAD mice in the spontaneous alternation Y-maze task. 5XFAD mice showed impairments in the hippocampal BDNF-TrkB pathway, as evidenced by significant reductions in BDNF, TrkB receptors, and phosphorylated TrkB. 7,8-DHF restored deficient TrkB signaling in 5XFAD mice without affecting endogenous BDNF levels. Meanwhile, 5XFAD mice exhibited elevations in the b-secretase enzyme (BACE1) that initiates amyloid-b (Ab) generation, as observed in sporadic AD. Interestingly, 7,8-DHF blocked BACE1 elevations and lowered levels of the b-secretasecleaved C-terminal fragment of amyloid precursor protein (C99), Ab40, and Ab42 in 5XFAD mouse brains. Furthermore, BACE1 expression was decreased by 7,8-DHF in wild-type mice, suggesting that BDNF-TrkB signaling is also important for downregulating baseline levels of BACE1. Together, our findings indicate that TrkB activation with systemic 7,8-DHF can ameliorate AD-associated memory deficits, which may be, at least in part, attributable to reductions in BACE1 expression and b-amyloidogenesis.

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“…The amyloid hypothesis is supported by the fact that mutation of APP or presenilins, the catalytic component of  secretase in APP processing, results in more production of A and early onset of familial Alzheimer's disease (FAD) [6,7] . A is found to be toxic in cultured cells and in animal models [8,9] , and inhibition of A production or enhancement of its clearance can attenuate the AD-like pathology [10,11] . The cleavage of APP by secretases is shown in Fig.…”

Section: Introductionmentioning

confidence: 99%

Regulation of β cleavage of amyloid precursor protein

2010

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Alzheimer's disease ranks the first cause for senile dementia. The amyloid cascade is proposed to contribute to the pathogenesis of this disease. In this cascade, amyloid  peptide (A) is produced through a sequential cleavage of amyloid precursor protein (APP) by  and  secretases, while its cleavage by  secretase precludes A production and generates neurotrophic sAPP. Thus, enhancing  secretase activity or suppressing  and  cleavage may reduce A formation and ameliorate the pathological process of the disease. Several regulatory mechanisms of APP cleavage have been established.The present review mainly summarizes the signaling pathways pertinent to the regulation of APP  cleavage.

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BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice

Cited by 267 publications

References 77 publications

APP mouse models for Alzheimer's disease preclinical studies

APP mouse models for Alzheimer's disease preclinical studies

7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease

Regulation of β cleavage of amyloid precursor protein

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