Mitochondrial Transfer Ameliorates Cognitive Deficits, Neuronal Loss, and Gliosis in Alzheimer’s Disease Mice

Nitzan, Keren; Benhamron, Sandrine; Valitsky, Michael; Kesner, Eyal E; Lichtenstein, Michal; Ben-Zvi, Ayal; Ella, Ezra; Segalstein, Yehudit; Saada, Ann; Lorberboum-Galski, Haya; Rosenmann, Hanna

doi:10.3233/jad-190853

Cited by 88 publications

(66 citation statements)

References 67 publications

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“…SZRD increases the hippocampal neurons in CA3 and DG of APP/PS1 transgenic mice AD's pathological feature is the loss of in hippocampal neurons [34]. Hippocampal neurons are the biological basis of hippocampal-dependent learning and memory.…”

Section: The Action Of Szrd In Ameliorating Cognitive Dysfunction In App/ps1 Transgenic Micementioning

confidence: 99%

Suan-Zao-Ren Decoction ameliorates synaptic plasticity through inhibition of the Aβ deposition and JAK2/STAT3 signaling pathway in AD model of APP/PS1 transgenic mice

Long

et al. 2021

Chin Med

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Background Suan-Zao-Ren Decoction (SZRD) has been widely used to treat neurological illnesses, including dementia, insomnia and depression. However, the mechanisms underlying SZRD’s improvement in cognitive function remain unclear. In this study, we examined SZRD’s effect on APP/PS1 transgenic mice and mechanisms associated with SZRD’s action in alleviating neuroinflammation and improving synaptic plasticity. Methods The APP/PS1 mice were treated with different dosages of SZRD (12.96 and 25.92 g/kg/day, in L-SZRD and H-SZRD groups, respectively) for 4 weeks. Morris water maze was conducted to determine changes in behaviors of the mice after the treatment. Meanwhile, in the samples of the hippocampus, Nissl staining and Golgi-Cox staining were used to detect synaptic plasticity. ELISA was applied to assess the expression levels of Aβ1−40 and Aβ1−42 in the hippocampus of mice. Western blot (WB) was employed to test the protein expression level of Aβ1−42, APP, ADAM10, BACE1, PS1, IDE, IBA1, GFAP, PSD95 and SYN, as well as the expressions of JAK2, STAT3 and their phosphorylation patterns to detect the involvement of JAK2/STAT3 pathway. Besides, we examined the serum and hippocampal contents of IL-1β, IL-6 and TNF-α through ELISA. Results Compared to the APP/PS1 mice without any treatment, SZRD, especially the L-SZRD, significantly ameliorated cognitive impairment of the APP/PS1 mice with decreases in the loss of neurons and Aβ plaque deposition as well as improvement of synaptic plasticity in the hippocampus (P < 0.05 or 0.01). Also, SZRD, in particular, the L-SZRD markedly inhibited the serum and hippocampal concentrations of IL-6, IL-1β and TNF-α, while reducing the expression of p-JAK2-Tyr1007 and p-STAT3-Tyr705 in the hippocampus of the APP/PS1 mice (P < 0.05 or 0.01). Conclusions The SZRD, especially the L-SZRD, may improve the cognitive impairment and ameliorate the neural degeneration in APP/PS1 transgenic mice through inhibiting Aβ accumulation and neuroinflammation via the JAK2/STAT3 pathway.

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Section: The Action Of Szrd In Ameliorating Cognitive Dysfunction In App/ps1 Transgenic Micementioning

confidence: 99%

Suan-Zao-Ren Decoction ameliorates synaptic plasticity through inhibition of the Aβ deposition and JAK2/STAT3 signaling pathway in AD model of APP/PS1 transgenic mice

Long

et al. 2021

Chin Med

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“…Restoration of mitophagy and inhibition of mitochondrial fission-promoting factor Drp1, whose interaction with Aβ results in defective mitophagy, might be beneficial for preventive neuronal death and cognitive deficits in Alzheimer’s type neurodegeneration [ 43 ]. However, some studies [ 44 ] have revealed that mitophagy is inhibited in neurons in Alzheimer’s disease, and stimulation of mitophagy might have a positive effect on the cognitive functions of experimental animals. Therefore, the exact role of aberrant mitophagy in neuronal damage in Alzheimer’s disease needs further clarification.…”

Section: Mitochondrial Dysfunction and Nvu/bbb Impairment In Alzheimer’s Type Neurodegenerationmentioning

confidence: 99%

Blood–Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration

Салмина

Kharitonova

Gorina

et al. 2021

IJMS

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Pathophysiology of chronic neurodegeneration is mainly based on complex mechanisms related to aberrant signal transduction, excitation/inhibition imbalance, excitotoxicity, synaptic dysfunction, oxidative stress, proteotoxicity and protein misfolding, local insulin resistance and metabolic dysfunction, excessive cell death, development of glia-supported neuroinflammation, and failure of neurogenesis. These mechanisms tightly associate with dramatic alterations in the structure and activity of the neurovascular unit (NVU) and the blood–brain barrier (BBB). NVU is an ensemble of brain cells (brain microvessel endothelial cells (BMECs), astrocytes, pericytes, neurons, and microglia) serving for the adjustment of cell-to-cell interactions, metabolic coupling, local microcirculation, and neuronal excitability to the actual needs of the brain. The part of the NVU known as a BBB controls selective access of endogenous and exogenous molecules to the brain tissue and efflux of metabolites to the blood, thereby providing maintenance of brain chemical homeostasis critical for efficient signal transduction and brain plasticity. In Alzheimer’s disease, mitochondria are the target organelles for amyloid-induced neurodegeneration and alterations in NVU metabolic coupling or BBB breakdown. In this review we discuss understandings on mitochondria-driven NVU and BBB dysfunction, and how it might be studied in current and prospective NVU/BBB in vitro models for finding new approaches for the efficient pharmacotherapy of Alzheimer’s disease.

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“…In addition to therapies attacking amyloid-beta, targeting mitochondrial dysfunction may indirectly ameliorate AD pathology. Nitzan and colleagues have attempted mitochondrial transplantation to restore mitochondrial function in a mouse AD model produced by Aβ 1-42 intracerebroventricular infusion (Nitzan et al, 2019). Mitochondria isolated from HeLa cells were injected through the tail vein.…”

Section: Alzheimer's Diseasementioning

confidence: 99%

“…Moreover, mitochondrial functional parameters in the liver and brain were also restored. Collectively, mitochondrial transplantation through IV route can be a new therapeutic strategy for AD (Nitzan et al, 2019).…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Extracellular Mitochondria Signals in CNS Disorders

Park

Hayakawa

2021

Front. Cell Dev. Biol.

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Mitochondria actively participate in the regulation of cell respiratory mechanisms, metabolic processes, and energy homeostasis in the central nervous system (CNS). Because of the requirement of high energy, neuronal functionality and viability are largely dependent on mitochondrial functionality. In the context of CNS disorders, disruptions of metabolic homeostasis caused by mitochondrial dysfunction lead to neuronal cell death and neuroinflammation. Therefore, restoring mitochondrial function becomes a primary therapeutic target. Recently, accumulating evidence suggests that active mitochondria are secreted into the extracellular fluid and potentially act as non-cell-autonomous signals in CNS pathophysiology. In this mini-review, we overview findings that implicate the presence of cell-free extracellular mitochondria and the critical role of intercellular mitochondrial transfer in various rodent models of CNS disorders. We also discuss isolated mitochondrial allograft as a novel therapeutic intervention for CNS disorders.

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Mitochondrial Transfer Ameliorates Cognitive Deficits, Neuronal Loss, and Gliosis in Alzheimer’s Disease Mice

Cited by 88 publications

References 67 publications

Suan-Zao-Ren Decoction ameliorates synaptic plasticity through inhibition of the Aβ deposition and JAK2/STAT3 signaling pathway in AD model of APP/PS1 transgenic mice

Suan-Zao-Ren Decoction ameliorates synaptic plasticity through inhibition of the Aβ deposition and JAK2/STAT3 signaling pathway in AD model of APP/PS1 transgenic mice

Blood–Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration

Extracellular Mitochondria Signals in CNS Disorders

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