Therapeutic Effects of Transplantation of As-MiR-937-Expressing Mesenchymal Stem Cells in Murine Model of Alzheimer's Disease

Background/Aims: Chronic stress can lead to cognitive impairment. Senescence-accelerated mouse prone 8 (SAMP8) is a naturally occurring animal model that is useful for investigating the neurological mechanisms of Alzheimer's disease. Here we investigated the impact and mechanisms of chronic stress on cognition in male SAMP8 mice. Methods: Male 6-month- old SAMP8 and SAMR1 (senescence-accelerated mouse resistant 1) mice strains were randomly divided into 4 groups. Mice in the unpredictable chronic mild stress (UCMS) groups were exposed to diverse stressors for 4 weeks. Then, these mice performed Morris water maze (MWM) test to assess the effect of UCMS on learning and memory. To explore the neurological mechanisms of UCMS on cognition in mice, we evaluated changes in the expression of postsynaptic density 95 (PSD95) and synaptophysin (SYN), which are essential proteins for synaptic plasticity. Five mice from each group were randomly chosen for reverse transcription polymerase chain reaction (RT-PCR) and western blotting analysis of SYN and PSD95. Results: The Morris water maze experiment revealed that the cognitive ability of the SAMP8 mice decreased with brain aging, and that chronic stress aggravated this cognitive deficit. In addition, chronic stress decreased the mRNA and protein expression of SYN and PSD95 in the hippocampus of the SAMP8 mice; however, the SAMR1 mice were unaffected. Conclusion: Our results demonstrate that decreased cognition and synaptic plasticity are related to aging. Moreover, we show that chronic stress aggravated this cognitive deficit and decreased SYN and PSD95 expression in the SAMP8 mice. Furthermore, the SAMP8 mice were more vulnerable to the detrimental effects of chronic stress on cognition than the SAMR1 mice. Our results suggest that the neurological mechanisms of chronic stress on cognition might be associated with a decrease in hippocampal SYN and PSD95 expression, which is critical for structural synaptic plasticity.

Section: Discussionmentioning

confidence: 99%

Effects of Chronic Stress on Cognition in Male SAMP8 Mice

Wang

Yuan²,

Pang³

et al. 2016

“…AD is characterized by severe cognitive impairments and progressive memory loss that affect the life and health of elderly people [1, 2]. The pathological characteristics of AD include the loss of pyramidal neurons, extracellular accumulation of senile plaques that contain amyloid-β (Aβ) deposits, and neurofibrillary tangles that contain hyper-phosphorylated tau [3, 4].…”

Section: Introductionmentioning

confidence: 99%

TRPML1 Participates in the Progression of Alzheimer’s Disease by Regulating the PPARγ/AMPK/Mtor Signalling Pathway

Zhang

Fang

Chen

et al. 2017

Background: TRPML1 is reported to be involved in the pathogenesis of Alzheimer’s disease (AD) by regulating autophagy; however, the underlying mechanism is not completely clear. Methods: We developed an APP/PS1 transgenic animal model that presents with AD. TRPML1 was also overexpressed in these mice. Protein expression levels were determined by Western blot. Morris water maze (MWM) and recognition tasks were performed to characterize cognitive ability. TUNEL assays were analysed for the detection of neuronal apoptosis. Primary neurons were isolated and treated with the vehicle, Aβ1-42 or Aβ1-42 + mTOR activator, as well as infected with the recombinant adenovirus TRPML1 overexpression vector in vitro. Cell viability was measured by the MTS assay, and lysosomal Ca²⁺ was also measured. Results: In the APP/PS1 transgenic mice, TRPML1 was downregulated, the PPARγ/AMPK signalling pathway was activated, the mTOR/S6K signalling pathway was suppressed, and autophagic lysosome reformation (ALR)-related proteins were upregulated. TRPML1 overexpression or treatment with PPARγ and AMPK inhibitors or an mTOR activator reduced the expression levels of ALR-related proteins, rescued the memory and recognition impairments and attenuated neuronal apoptosis in mice with the APP/PS1 transgenes. In vitro experiments showed that TRPML1 overexpression or treatment with the mTOR activator propranolol attenuated the Aβ1-42-suppressed cell viability and the Aβ1-42-decreased lysosomal [Ca²⁺] ion concentration in primary neurons. TRPML1 overexpression or treatment with the mTOR activator propranolol also attenuated the Aβ1-42-inhibited mTOR/S6K signalling pathway and the Aβ1-42-induced ALR-related protein expression levels. Conclusion: TRPML1 is involved in the pathogenesis of AD by regulating autophagy at least in part through the PPARγ/AMPK/mTOR signallingpathway.

“…Thus, very recent approaches have been applied to modify gene expression of MSCs, using successful experiences from studies of other fields. For example, Liu et al showed that during treating mouse model of Alzheimer’s disease with MSCs, depletion of miR-937 in MSCs significantly reduced the deposition of Abeta, increased the levels of BDNF, and significantly improved the therapeutic outcome in mice [22]. In another study, Yan et al reported that transplantation of AAV carrying as-miR-548e partially mimicked the effects of MSC transplantation on collagen-induced arthritis in mice, possibly through suppressing miR-548e-mediated IkappaB inhibition [23].…”

Section: Discussionmentioning

confidence: 99%

Suppression of MicroRNA-383 Enhances Therapeutic Potential of Human Bone-Marrow-Derived Mesenchymal Stem Cells in Treating Spinal Cord Injury via GDNF

Wei

An²,

Shi

et al. 2017

Background/Aims: Transplantation of bone-marrow-derived mesenchymal stem cells (MSCs) has been used to treat spinal cord injury (SCI) to enhance tissue repair and neural cell regeneration. Glial cell line derived neurotrophic factor (GDNF) is an identified neural growth and survival factor. Here, we examined whether modification of GDNF levels in MSCs may further increase the potential of MSCs in promoting neural cell regeneration and subsequently the therapeutic outcome. Methods: We examined the mRNA and protein levels of GDNF in human MSCs by RT-qPCR and Western blot, respectively. Bioinformatics analyses were done to predict microRNAs (miRNAs) that target GDNF in MSCs. The functional binding of miRNAs to GDNF mRNA was examined by a dual luciferase reporter assay. MSCs were transduced with adeno-associated virus (AAV) carrying null or antisense for miR-383 (as-miR-383), which were transplanted into nude rats that underwent SCI. The intact tissue, cavity volume, and recovery of locomotor activity were assessed. Results: MSCs expressed very low GDNF protein, but surprisingly high levels of GDNF mRNA. Bioinformatics analyses showed that miR-383 inhibited protein translation of GDNF, through binding to the 3’-UTR of the GDNF mRNA. MSCs transduced with AAV-as-miR-383 further increased the intact tissue percentage, decreased cavity volume, and enhanced the recovery of locomotor activity in nude rats that underwent SCI, compared to MSCs. Conclusions: Suppression of miR-383 may increase the therapeutic potential of human bone-marrow-derived MSCs in treating SCI via augmentation of GDNF protein levels.