Potential for Stem Cells Therapy in Alzheimer’s Disease: Do Neurotrophic Factors Play Critical Role?

Alzheimer’s disease (AD) is one of the most common causes of dementia. Despite several decades of research in AD, there is no standard disease- modifying therapy available and currentlyapproved drugs provide only symptomatic relief. Stem cells hold immense potential to regenerate damaged tissues and are currently tested in some brain-related disorders, such as AD, amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). We review stem cell transplantation studies using preclinical and clinical tools. We describe different sources of stem cells used in various animal models and explaining the putative molecular mechanisms that can rescue neurodegenerative disorders. The clinical studies suggest safety, efficacy and translational potential of stem cell therapy. The therapeutic outcome of stem cell transplantation has been promising in many studies, but no unifying hypothesis can convincingly explain the underlying mechanism. Some studies have reported paracrine effects exerted by these stem cells via the release of neurotrophic factors, while other studies describe the immunomodulatory effects exerted by the transplanted cells. There are also reports which indicate that stem cell transplantation might result in endogenous cell proliferation or replacement of diseased cells. In animal models of AD, stem cell transplantation is also believed to increase expression of synaptic proteins

CD34 and CD117 Stemness of Lineage-Negative Cells Reverses Memory Loss Induced by Amyloid Beta in Mouse Model

A majority of the neurodegenerative disorders including Alzheimer's disease are untreatable and occur primarily due to aging and rapidly changing lifestyles. The rodent Alzheimer's disease models are critical for investigating the underlying disease pathology and screening of novel therapeutic targets in preclinical settings. We aimed to characterize the stemness properties of human umbilical cord blood (hUCB) derived lineage-negative (Lin−) stem cells based on CD34 and CD117 expression as well as surface morphology using flow cytometry and scanning electron microscopy, respectively. The efficacy of the stem cells was tested by its capacity to rescue the injury caused by intrahippocampal delivery of varying doses of amyloid beta. The hUCB Lin− stem cells reversed memory loss due to Aβ42-induced injury more effectively at micromolar concentration, and not picomolar concentration. More studies are required to delineate the underlying molecular events associated with hUCB Lin− stem cells

Neuroprotective effect of MK-801 against intra-striatal quinolinic acid induced behavioral, oxidative stress and cellular alterations in rats

880-892 Huntington’s Disease (HD) is a common neurodegenerative disorder characterized by motor disturbances, subcortical dementia and psychiatric disturbances. Pathogenesis of HD revolves so far around excitatory amino acids as the primary cause of neuronal loss. However, number of recent reports suggests the involvement of excitotoxicity and oxidative damage. In the present study, first the dose of quinolinic acid that mimics the symptoms of HD was standardized and then the neuroprotective effect of MK-801 (noncompetitive NMDAr antagonist) was evaluated against intrastriatalquinolinic acid induced behavioral, oxidative stress and cellular alterations in rats. A single unilateral (ipsilateral striatum) injections of quinolinic acid (100, 200 and 300 nM) were made in to striatum. Animals were tested for motor functions using actophotometer and rotarod apparatus. Quinolinic acid (300 nM) significantly reduced the body weight and caused motor in-coordination and produced oxidative damage in the cortex and striatum as indicated by raised lipid peroxidation, nitrite concentration, depletion of superoxide dismutase, catalase and different glutathione levels. Beside, quinolinic acid (300 nM) significantly altered the mitochondrial enzymes complex levels and caused histopathological alterations in the striatum. MK-801(0.02, 0.04, 0.08 mg/kg, ip) treatment significantly improved body weight, behavioral alterations (locomotor activity and rotarod performance) and attenuated oxidative damage and mitochondrial enzymes complex dysfunction. Besides, MK-801 treatment significantly reversed histopathological alterations in striatum. The results suggest antioxidant and neuroprotective action of MK-801 against the quinolinic acid induced Huntington’s like behavioral, oxidative stress and cellular alterations in rats. </smarttagtype

Molecular interactions of resveratrol with Aβ 42 peptide and fibril during in-vitro Aβ 42 aggregation

Amyloid aggregates are responsible for the development of oxidative stress and neurotoxicity in the brain. Several amino acid residues of amyloid beta (Aβ) 42 establish different molecular interactions to form and stabilize these aggregates, which can be targeted to prevent the aggregation. Resveratrol (Res) has inhibitory properties against Aβ 42 aggregation but studies elucidating its interactions with different residues of Aβ 42 aggregates are scarce. In the present study, we have discerned the molecular interactions of Res with different amino acid residues of Aβ 42 peptide and fibril during in-vitro Aβ 42 aggregation. Inhibitory properties of Res against amyloid aggregation were established through ANS and Thioflavin-T fluorescence assay, congo red assay and CD spectroscopy. The molecular interactions were established through molecular docking and 100 ns molecular dynamics simulations. The hydrophobic regions of Aβ 42 peptide, responsible for the formation of aggregates, were better protected in the presence of Res as indicated by ANS assay. Th-T and congo red assay suggested that Res prevented the formation of cross β-sheet structures. CD spectra analysis revealed that in the presence of Res, the secondary structure content was significantly decreased. MD simulation analysis revealed that Res formed strong molecular interactions with hydrophobic and secondary structure forming amino acid residues, which are involved in the amyloid aggregation and stabilization of aggregates. In conclusion, these interactions might have led to the decline in secondary structure content, formation of unordered nontoxic aggregates and prevention of the formation of sufuranyl free radical