BACE1 Deficiency Rescues Memory Deficits and Cholinergic Dysfunction in a Mouse Model of Alzheimer's Disease

Ohno, Minoru; Sametsky, Evgeny A.; Younkin, Linda H.; Oakley, Holly D.; Younkin, Steven G.; Citron, Martin; Vassar, Robert; Disterhoft, John F.

doi:10.1016/s0896-6273(03)00810-9

Cited by 493 publications

(415 citation statements)

References 61 publications

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“…BACE1 deficiency precludes A␤ formation in transgenic mice (2) and does not cause or promote any neurological or phenotypic abnormalities. Moreover, BACE1 inactivation rescues memory deficits in transgenic mice (3), strongly supporting the importance of BACE1 as a therapeutic target in AD.…”

mentioning

confidence: 74%

Nonsteroidal anti-inflammatory drugs repress β-secretase gene promoter activity by the activation of PPARγ

Sastre

Dewachter

Rößner

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

343

242

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Epidemiological evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the risk for Alzheimer's disease (AD). Certain NSAIDs can activate the peroxisome proliferatoractivated receptor-␥ (PPAR␥), which is a nuclear transcriptional regulator. Here we show that PPAR␥ depletion potentiates ␤-secretase [␤-site amyloid precursor protein cleaving enzyme (BACE1)] mRNA levels by increasing BACE1 gene promoter activity. Conversely, overexpression of PPAR␥, as well as NSAIDs and PPAR␥ activators, reduced BACE1 gene promoter activity. These results suggested that PPAR␥ could be a repressor of BACE1. We then identified a PPAR␥ responsive element (PPRE) in the BACE1 gene promoter. Mutagenesis of the PPRE abolished the binding of PPAR␥ to the PPRE and increased BACE1 gene promoter activity. Furthermore, proinflammatory cytokines decreased PPAR␥ gene transcription, and this effect was supressed by NSAIDs. We also demonstrate that in vivo treatment with PPAR␥ agonists increased PPAR␥ and reduced BACE1 mRNA and intracellular ␤-amyloid levels. Interestingly, brain extracts from AD patients showed decreased PPAR␥ expression and binding to PPRE in the BACE1 gene promoter. Our data strongly support a major role of PPAR␥ in the modulation of amyloid-␤ generation by inflammation and suggest that the protective mechanism of NSAIDs in AD involves activation of PPAR␥ and decreased BACE1 gene transcription.amyloid ͉ inflammation ͉ Alzheimer's disease ͉ transgenic mice

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mentioning

confidence: 74%

Nonsteroidal anti-inflammatory drugs repress β-secretase gene promoter activity by the activation of PPARγ

Sastre

Dewachter

Rößner

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

343

242

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“…We tested the effects of TMAO on spatial working memory in mice with the Y‐maze (Kimura, Devi & Ohno, 2010; Ohno et al., 2004) (Figure 2a–d). There was no significant difference among the four groups in the total number of arms entered, which indicated the mice in the four groups had similar working memories (Figure 2a).…”

Section: Resultsmentioning

confidence: 99%

Trimethylamine‐N‐oxide promotes brain aging and cognitive impairment in mice

et al. 2018

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SummaryGut microbiota can influence the aging process and may modulate aging‐related changes in cognitive function. Trimethylamine‐N‐oxide (TMAO), a metabolite of intestinal flora, has been shown to be closely associated with cardiovascular disease and other diseases. However, the relationship between TMAO and aging, especially brain aging, has not been fully elucidated. To explore the relationship between TMAO and brain aging, we analysed the plasma levels of TMAO in both humans and mice and administered exogenous TMAO to 24‐week‐old senescence‐accelerated prone mouse strain 8 (SAMP8) and age‐matched senescence‐accelerated mouse resistant 1 (SAMR1) mice for 16 weeks. We found that the plasma levels of TMAO increased in both the elderly and the aged mice. Compared with SAMR1‐control mice, SAMP8‐control mice exhibited a brain aging phenotype characterized by more senescent cells in the hippocampal CA3 region and cognitive dysfunction. Surprisingly, TMAO treatment increased the number of senescent cells, which were primarily neurons, and enhanced the mitochondrial impairments and superoxide production. Moreover, we observed that TMAO treatment increased synaptic damage and reduced the expression levels of synaptic plasticity‐related proteins by inhibiting the mTOR signalling pathway, which induces and aggravates aging‐related cognitive dysfunction in SAMR1 and SAMP8 mice, respectively. Our findings suggested that TMAO could induce brain aging and age‐related cognitive dysfunction in SAMR1 mice and aggravate the cerebral aging process of SAMP8 mice, which might provide new insight into the effects of intestinal microbiota on the brain aging process and help to delay senescence by regulating intestinal flora metabolites.

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“…Spontaneous alternation performance was tested using a symmetrical Y-maze, as described previously (Kimura et al, 2010;Ohno et al, 2004). Each mouse was placed in the center of the Y-maze and was allowed to explore freely through the maze during an 8-min session.…”

Section: Spontaneous Alternation Y-maze Testmentioning

confidence: 99%

“…5XFAD mice at 12-15 months of age and their wild-type littermate controls received repeated injections of 7,8-DHF (5 mg/kg, i.p.) or vehicle (17% DMSO) once daily for 10 consecutive days, and were tested with the spontaneous alternation Y-maze paradigm that assesses spatial working memory function (Lalonde, 2002;Ohno et al, 2004). The dosage of 7,8-DHF was determined based on previous in vivo studies demonstrating that systemic administration of this compound activates central TrkB receptors and rescues memory deficits in BDNF-knockout mice (Choi et al, 2010;Jang et al, 2010).…”

Section: Systemic 78-dhf Ameliorates Memory Deficits In 5xfad Micementioning

confidence: 99%

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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BACE1 Deficiency Rescues Memory Deficits and Cholinergic Dysfunction in a Mouse Model of Alzheimer's Disease

Cited by 493 publications

References 61 publications

Nonsteroidal anti-inflammatory drugs repress β-secretase gene promoter activity by the activation of PPARγ

Nonsteroidal anti-inflammatory drugs repress β-secretase gene promoter activity by the activation of PPARγ

Trimethylamine‐N‐oxide promotes brain aging and cognitive impairment in mice

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

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