Regenerating the brain: Stem cell differentiation and cholinergic dysfunction in Alzheimer disease

Hippocampal neurogenesis in the adult brain is important for learning and memory processes, which are heavily affected in Alzheimer disease (AD). Thus, targeting processes that could stimulate neurogenesis is a logical step in the search for strategies offering neuronal renewal and brain repair. However, the pathological lesions in the AD brain start to accumulate decades before the onset of clinical symptoms and neuronal plasticity is likely to be compromised by the pathological burden. The aim of this thesis was to provide a deeper understanding of how pathological mechanisms in AD affect stem cell differentiation and cholinergic signaling mechanisms, with implications for future regenerative therapies. The progressive loss of cholinergic neurons in AD may be a consequence of accumulation of β-amyloid (Aβ) in the brain. In paper I, there were prevailing differences in Aβ assemblies between early onset AD and late onset AD and that reduced cholinergic activity correlated with distinct Aβ oligomers. In paper II, the impact of nerve growth factor (NGF) and Aβ treatment on the development of cholinergic neurons from human embryonic stem (hES) cells was investigated. NGF treatment increased differentiation into functional cholinergic neurons, oligomeric Aβ treatment decreased the number of functional neurons, and fibrillar Aβ promoted glial differentiation. In paper III, fibrillar Aβ treatment altered the secretion of cholinergic enzymes from hES cells, resulting in low levels of acetylcholine. These changes were linked with an altered secretion pattern for cytokines, reduced neuronal differentiation and increased gliogenesis. In paper IV, the effects of hippocampal human neural stem cell transplantation alone, or in combination and modulation of Aβ levels with (+)-phenserine or the partial α7 nicotinic acetylcholine receptor (nAChR) agonist JN403 on neurogenesis, graft survival, astrocytosis and cognitive performance in young Tg2576 mice (representing the early stages of AD) was studied. Neural stem cell transplantation increased endogenous neurogenesis and reduced memory impairment in AD mice not receiving the drugs but not in those receiving the drugs. JN403 decreased the number of α7 nAChR-expressing astrocytes, which correlated with reduced neurogenesis. We thus hypothesize that α7 nAChR-expressing astrocytes are involved in neurogenic processes during the development of neuropathology. It is hoped that the findings presented in this thesis will provide novel targets for further studies, with potential for stimulating neuronal regeneration in AD

Neural Stem Cell Transplant-Induced Effect on Neurogenesis and Cognition in Alzheimer Tg2576 Mice Is Inhibited by Concomitant Treatment with Amyloid-Lowering or Cholinergic α7 Nicotinic Receptor Drugs.

Stimulating regeneration in the brain has the potential to rescue neuronal networks and counteract progressive pathological changes in Alzheimer's disease (AD). This study investigated whether drugs with different mechanisms of action could enhance neurogenesis and improve cognition in mice receiving human neural stem cell (hNSC) transplants. Six- to nine-month-old AD Tg2576 mice were treated for five weeks with the amyloid-modulatory and neurotrophic drug (+)-phenserine or with the partial α7 nicotinic receptor (nAChR) agonist JN403, combined with bilateral intrahippocampal hNSC transplantation. We observed improved spatial memory in hNSC-transplanted non-drug-treated Tg2576 mice but not in those receiving drugs, and this was accompanied by an increased number of Doublecortin- (DCX-) positive cells in the dentate gyrus, a surrogate marker for newly generated neurons. Treatment with (+)-phenserine did however improve graft survival in the hippocampus. An accumulation of α7 nAChR-expressing astrocytes was observed around the injection site, suggesting their involvement in repair and scarring processes. Interestingly, JN403 treatment decreased the number of α7 nAChR-expressing astrocytes, correlating with a reduction in the number of DCX-positive cells in the dentate gyrus. We conclude that transplanting hNSCs enhances endogenous neurogenesis and prevents further cognitive deterioration in Tg2576 mice, while simultaneous treatments with (+)-phenserine or JN403 result in countertherapeutic effects

Processing of nanostructured polymers and advanced polymeric based nanocomposites

The control of the nanostructure and the addition of nanoparticles to polymers have led to structural and functional property enhancements in a number of polymeric systems as a material answer to continuous requirements from advanced industrial sectors. The availability of new nanoparticles with extraordinary properties (i.e. carbon nanotubes, graphenes, but also nanoclays, nanocellulose, metals and ceramics) have determined new and exciting possibilities for a continuous enlargement of polymer markets. However, the potentialities of these new materials are still strongly dependent on the development and scaling-up of reliable processing routes. Therefore, the purpose of this report is to review the main processing approaches for nanostructured polymers and nanocomposites starting with a brief review of available nanoparticles and on their functionalization to promote a better polymer-particle interaction. Regarding processing, the review firstly addresses the bottom-up approaches typically adopted for nanostructured polymers, blends and copolymers. Then, the different technologies required by the top-down processing of thermoplastic and thermosetting polymer matrix systems are reviewed. Finally, the report addresses the recent applications of nanostructured polymers and nanocomposites as matrices of advanced composite materials. In all cases, the main processing approaches and the main structural and functional properties characterizing these materials and their potential and current industrial applications are specifically addressed.We are indebted to the Spanish Ministry of Economy and Competitiveness (MINECO) for their economic support of this research (MAT2013-48059-C2-1-R). LP acknowledges the support of a JAEDoc grant from CSIC cofinanced by FSE. JMK acknowledges the support of the Russian Ministry of Education and Science within State Contract No. 14.Z50.31.0002.Peer Reviewe