Co-Administration of TiO2 Nanowired Mesenchymal Stem Cells with Cerebrolysin Potentiates Neprilysin Level and Reduces Brain Pathology in Alzheimer’s Disease

Abstract

Neprilysin (NPL), the rate-limiting enzyme for amyloid beta peptide (AβP), appears to play a crucial role in the pathogenesis of Alzheimer's disease (AD). Since mesenchymal stem cells (MSCs) and/or cerebrolysin (CBL, a combination of neurotrophic factors and active peptide fragments) have neuroprotective effects in various CNS disorders, we examined nanowired delivery of MSCs and CBL on NPL content and brain pathology in AD using a rat model. AD-like symptoms were produced by intraventricular (i.c.v.) administration of AβP (1-40) in the left lateral ventricle (250 ng/10 μl, once daily) for 4 weeks. After 30 days, the rats were examined for NPL and AβP concentrations in the brain and related pathology. Co-administration of TiO2-nanowired MSCs (10 cells) with 2.5 ml/kg CBL (i.v.) once daily for 1 week after 2 weeks of AβP infusion significantly increased the NPL in the hippocampus (400 pg/g) from the untreated control group (120 pg/g; control 420 ± 8 pg/g brain) along with a significant decrease in the AβP deposition (45 pg/g from untreated control 75 pg/g; saline control 40 ± 4 pg/g). Interestingly, these changes were much less evident when the MSCs or CBL treatment was given alone. Neuronal damages, gliosis, and myelin vesiculation were also markedly reduced by the combined treatment of TiO2, MSCs, and CBL in AD. These observations are the first to show that co-administration of TiO2-nanowired CBL and MSCs has superior neuroprotective effects in AD probably due to increasing the brain NPL level effectively, not reported earlier.

Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy

“…Not only was this effective in the regions where the stem cells were grafted (amygdala and septum) (Blurton‐Jones et al, ). Variants of these procedures have confirmed the viability of this stem cell approach in various animal models (Sharma et al, ).…”

Cerebrolysin in the therapy of mild cognitive impairment and dementia due to Alzheimer's disease: 30 years of clinical use

“…The PI3K/Akt signaling pathway and enzymes such as GSK3β, CDK5, BACE1 (APP β-secretase) and the Aβ degrading enzyme Neprilysin have been involved in the reductions of Aβ and Tau pathology induced by Cerebrolysin, and in some of its neuroprotective effects. [149][150][151][152][153][154][155][156] Cerebrolysin counteracts LPS-induced changes in brain NF-κB, JNK, and p38-MAPK signaling, improving brain recovery and functioning. 157,158 These signaling pathways contributed to the switch of microglia to an antiinflammatory phenotype and to the decrease of inflammation factors (TNF-α and IL-1β), and might also be involved in the anti-inflammatory effects of Cerebrolysin in other experimental conditions and in AD patients.…”

“…142,157,164,166,179,[186][187][188][189][190] The expression of GLUT1 glucose transporter and the transport of glucose through the BBB were also enhanced by Cerebrolysin. 142,191,192 Finally, Cerebrolysin regulates the expression of caspases and other apoptosis/autophagyrelated factors [154][155][156][157]164,167,184,193,194 ; the levels of dendritic microtubule-associated protein-2 (MAP2) and of synaptic proteins involved in neuroplasticity [150][151][152][153]175,[194][195][196] ; and the activity of the sonic hedgehog signaling pathway, implicated in neurogenesis and neurorestoration. 197…”

“…[150][151][152][153][154][155][156][157][193][194][195][196][197] All these molecular mechanisms contribute to the positive influence of Cerebrolysin on AD-related processes of cellular protection and functional recovery. Cerebrolysin ameliorates Aβ and tau neuropathology [150][151][152][153][154][155][156]195,198 ; modulates the activation of microglial cells, switching microglia to an anti-inflammatory phenotype [157][158][159][160][161][162][163] ; protects against mitochondrial disruption, improving energy and detox metabolism 153,[180][181][182][183][184][185] ; enhances neuroplasticity, preventing synaptic and dendritic loss 189,[193][194][195][196][197] ; supports neurogenesis 146,149,193,…”

On the Interaction between 1D Materials and Living Cells

“…Whereas the administration of rat MSCs (1 × 10 6 ) to diabetic rats slightly reduced the brain injury, TiO 2 nanowired MSCs led to complete neuroprotection. The same group investigated the nanowired delivery of MSCs and cerebrolysin (a mixture of neurotrophic peptides) evaluating their effects on Alzheimer diseases in the rat model [ 105 ]. The TiO 2 -nanowired MSCs (10 6 cells) in synergy with cerebrolysin increased the level of neprilysin, the key enzyme for beta amyloid peptide degradation.…”