Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease

Ji, Lin; Piña‐Crespo, Juan C.; Li, Yonghe

doi:10.1186/s13041-019-0525-5

Cited by 204 publications

(164 citation statements)

References 183 publications

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“…The Wnt/β-catenin signaling pathway has been considered a potential therapeutic target in preventing cell death for an extensive amount of time [ 18 , 40 , 41 ]. The down-regulation of Wnt ligands and increased antagonistic activity have been observed in neurodegenerative and excitotoxic disorders [ 42 , 43 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

Lipid Emulsion Improves Functional Recovery in an Animal Model of Stroke

Tanioka

Park

et al. 2020

IJMS

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Stroke is a life-threatening condition that leads to the death of many people around the world. Reperfusion injury after ischemic stroke is a recurrent problem associated with various surgical procedures that involve the removal of blockages in the brain arteries. Lipid emulsion was recently shown to attenuate ischemic reperfusion injury in the heart and to protect the brain from excitotoxicity. However, investigations on the protective mechanisms of lipid emulsion against ischemia in the brain are still lacking. This study aimed to determine the neuroprotective effects of lipid emulsion in an in vivo rat model of ischemic reperfusion injury through middle cerebral artery occlusion (MCAO). Under sodium pentobarbital anesthesia, rats were subjected to MCAO surgery and were administered with lipid emulsion through intra-arterial injection during reperfusion. The experimental animals were assessed for neurological deficit wherein the brains were extracted at 24 h after reperfusion for triphenyltetrazolium chloride staining, immunoblotting and qPCR. Neuroprotection was found to be dosage-dependent and the rats treated with 20% lipid emulsion had significantly decreased infarction volumes and lower Bederson scores. Phosphorylation of Akt and glycogen synthase kinase 3-β (GSK3-β) were increased in the 20% lipid-emulsion treated group. The Wnt-associated signals showed a marked increase with a concomitant decrease in signals of inflammatory markers in the group treated with 20% lipid emulsion. The protective effects of lipid emulsion and survival-related expression of genes such as Akt, GSK-3β, Wnt1 and β-catenin were reversed by the intra-peritoneal administration of XAV939 through the inhibition of the Wnt/β-catenin signaling pathway. These results suggest that lipid emulsion has neuroprotective effects against ischemic reperfusion injury in the brain through the modulation of the Wnt signaling pathway and may provide potential insights for the development of therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Lipid Emulsion Improves Functional Recovery in an Animal Model of Stroke

Tanioka

Park

et al. 2020

IJMS

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“…In turn, Aβ was identified to increase osteoclast activation and bone resorption [ 81 ]. Thus, targeting of Aβ plaques may evolve as a promising therapeutic approach to prevent cognitive decline and bone loss in patients with AD [ 82 ].…”

Section: Clinical Observationsmentioning

confidence: 99%

“…Therefore, the inhibition of sclerostin was proposed as a therapeutic approach in the treatment of bone loss [ 349 ], which led to the development and approval in the US and Europe of the monoclonal sclerostin-antibody Romosozumab for severe osteoporosis [ 350 , 351 , 352 , 353 ]. In the brain, Wnt/β-catenin signaling is essential for neurogenesis, neuronal survival, synaptic plasticity, BBB integrity [ 82 ] and further associated with the pathophysiology of AD [ 354 ]. As SOST /sclerostin is expressed by several other tissues in physiological and pathogenic conditions [ 355 ], additional studies are required to elucidate whether pharmacologic inhibition of sclerostin may also affect Wnt/β-catenin signaling in the brain [ 8 ].…”

Section: Molecular Bases Of Brain-bone Crosstalkmentioning

confidence: 99%

Crosstalk of Brain and Bone—Clinical Observations and Their Molecular Bases

Otto

Knapstein

Jahn

et al. 2020

IJMS

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As brain and bone disorders represent major health issues worldwide, substantial clinical investigations demonstrated a bidirectional crosstalk on several levels, mechanistically linking both apparently unrelated organs. While multiple stress, mood and neurodegenerative brain disorders are associated with osteoporosis, rare genetic skeletal diseases display impaired brain development and function. Along with brain and bone pathologies, particularly trauma events highlight the strong interaction of both organs. This review summarizes clinical and experimental observations reported for the crosstalk of brain and bone, followed by a detailed overview of their molecular bases. While brain-derived molecules affecting bone include central regulators, transmitters of the sympathetic, parasympathetic and sensory nervous system, bone-derived mediators altering brain function are released from bone cells and the bone marrow. Although the main pathways of the brain-bone crosstalk remain ‘efferent’, signaling from brain to bone, this review emphasizes the emergence of bone as a crucial ‘afferent’ regulator of cerebral development, function and pathophysiology. Therefore, unraveling the physiological and pathological bases of brain-bone interactions revealed promising pharmacologic targets and novel treatment strategies promoting concurrent brain and bone recovery.

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“…Paraquat exposure altered the levels of the Wnt pathway genes in mouse neural progenitor cells [106], rotenone impaired Wnt signaling in a Drosophila PD model [107] and Deltamethrin also reduced Wnt signaling pathway genes in zebrafish's development of swim bladder [108]. Wnt signaling is known to be impaired in AD [109][110][111], and activation of the Wnt/β-catenin signaling pathway represses BACE-1 expression [112]. Activation of Wnt signaling has been shown to rescue memory loss and improves synaptic dysfunction in APP/PS1 AD transgenic mice [113,114].…”

Section: Enhancement Of Aβ and Tau Expression Modification And Clearmentioning

confidence: 99%

Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease

Tang

2020

Toxics

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Environmental toxicants have been implicated in neurodegenerative diseases, and pesticide exposure is a suspected environmental risk factor for Alzheimer’s disease (AD). Several epidemiological analyses have affirmed a link between pesticides and incidence of sporadic AD. Meanwhile, in vitro and animal models of AD have shed light on potential neuropathological mechanisms. In this paper, a perspective on neuropathological mechanisms underlying pesticides’ induction of AD is provided. Proposed mechanisms range from generic oxidative stress induction in neurons to more AD-specific processes involving amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau). Mechanisms that are more speculative or indirect in nature, including somatic mutation, epigenetic modulation, impairment of adult neurogenesis, and microbiota dysbiosis, are also discussed. Chronic toxicity mechanisms of environmental pesticide exposure crosstalks in complex ways and could potentially be mutually enhancing, thus making the deciphering of simplistic causal relationships difficult.

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Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease

Cited by 204 publications

References 183 publications

Lipid Emulsion Improves Functional Recovery in an Animal Model of Stroke

Lipid Emulsion Improves Functional Recovery in an Animal Model of Stroke

Crosstalk of Brain and Bone—Clinical Observations and Their Molecular Bases

Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease

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