Cognitive and Histopathological Alterations in Rat Models of Early- and Late-Phase Memory Dysfunction: Effects of Sigma-1 Receptor Activation.

Background: Sigma-1 receptors are highly expressed in brain areas related to cognitive function and are a promising target for anti-amnesic treatments. We previously showed that activation of sigma-1 receptors by the selective agonist compound methyl(1 R,2 S/1 S,2 R)-2-[4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl) cyclopropane carboxylate [(±)-PPCC] promotes a remarkable recovery in rat models of memory loss associated to cholinergic dysfunction. Objective: In this study, we sought to assess the role of (±)-PPCC on working memory deficits caused by noradrenergic depletion. Methods: Animals with a mild or severe working memory deficits associated to varying degrees of noradrenergic neuronal depletion were treated with the sigma-1 agonist just prior to the beginning of each behavioral testing session. Results: While (±)-PPCC alone at a dose of 1 mg/kg/day failed to affect working memory in lesioned animals, its association with the α2 adrenergic receptor agonist clonidine, completely blocked noradrenaline release, significantly improving rat performance. This effect, distinct from noradrenaline activity, is likely to result from a direct action of the (±)-PPCC compound onto sigma-1 receptors, as pre-treatment with the selective sigma-1 receptor antagonist BD-1047 reversed the improved working memory performance. Despite such clear functional effects, the treatment did not affect noradrenergic neuron survival or terminal fiber proliferation. Conclusions: Future studies are thus necessary to address the effects of long-lasting (±)-PPCC treatment, with or without clonidine, on cognitive abilities and Alzheimer's disease-like histopathology. Considering the already established involvement of sigma-1 receptors in endogenous cell plasticity mechanisms, their activation by selective agonist compounds holds promises as possibly positive contributor to disease-modifying events in neurodegenerative diseases.

Mitigating the Functional Deficit after Neurotoxic Motoneuronal Loss by an Inhibitor of Mitochondrial Fission.

Amyotrophic lateral sclerosis (ALS) is an extremely complex neurodegenerative disease involving different cell types, but motoneuronal loss represents its main pathological feature. Moreover, compensatory plastic changes taking place in parallel to neurodegeneration are likely to affect the timing of ALS onset and progression and, interestingly, they might represent a promising target for disease-modifying treatments. Therefore, a simplified animal model mimicking motoneuronal loss without the other pathological aspects of ALS has been established by means of intramuscular injection of cholera toxin-B saporin (CTB-Sap), which is a targeted neurotoxin able to kill motoneurons by retrograde suicide transport. Previous studies employing the mouse CTB-Sap model have proven that spontaneous motor recovery is possible after a subtotal removal of a spinal motoneuronal pool. Although these kinds of plastic changes are not enough to counteract the functional effects of the progressive motoneuron degeneration, it would nevertheless represent a promising target for treatments aiming to postpone ALS onset and/or delay disease progression. Herein, the mouse CTB-Sap model has been used to test the efficacy of mitochondrial division inhibitor 1 (Mdivi-1) as a tool to counteract the CTB-Sap toxicity and/or to promote neuroplasticity. The homeostasis of mitochondrial fission/fusion dynamics is indeed important for cell integrity, and it could be affected during neurodegeneration. Lesioned mice were treated with Mdivi-1 and then examined by a series of behavioral test and histological analyses. The results have shown that the drug may be capable of reducing functional deficits after the lesion and promoting synaptic plasticity and neuroprotection, thus representing a putative translational approach for motoneuron disorders.

Selective Noradrenaline Depletion in the Neocortex and Hippocampus Induces Working Memory Deficits and Regional Occurrence of Pathological Proteins.

Noradrenaline (NA) depletion occurs in Alzheimer's disease (AD); however, its relationship with the pathological expression of Tau and transactive response DNA-binding protein 43 (TDP-43), two major hallmarks of AD, remains elusive. Here, increasing doses of a selective noradrenergic immunotoxin were injected into developing rats to generate a model of mild or severe NA loss. At about 12 weeks post-lesion, dose-dependent working memory deficits were detected in these animals, associated with a marked increase in cortical and hippocampal levels of TDP-43 phosphorylated at Ser 409/410 and Tau phosphorylated at Thr 217. Notably, the total levels of both proteins were largely unaffected, suggesting a direct relationship between neocortical/hippocampal NA depletion and the phosphorylation of pathological Tau and TDP-43 proteins. As pTD43 is present in 23% of AD cases and pTau Thr217 has been detected in patients with mild cognitive impairment that eventually would develop into AD, improvement of noradrenergic function in AD might represent a viable therapeutic approach with disease-modifying potential.

Hippocampal Noradrenaline Is a Positive Regulator of Spatial Working Memory and Neurogenesis in the Rat.

Loss of noradrenaline (NA)-rich afferents from the Locus Coeruleus (LC) ascending to the hippocampal formation has been reported to dramatically affect distinct aspects of cognitive function, in addition to reducing the proliferation of neural progenitors in the dentate gyrus. Here, the hypothesis that reinstating hippocampal noradrenergic neurotransmission with transplanted LC-derived neuroblasts would concurrently normalize both cognitive performance and adult hippocampal neurogenesis was investigated. Post-natal day (PD) 4 rats underwent selective immunolesioning of hippocampal noradrenergic afferents followed, 4 days later, by the bilateral intrahippocampal implantation of LC noradrenergic-rich or control cerebellar (CBL) neuroblasts. Starting from 4 weeks and up to about 9 months post-surgery, sensory-motor and spatial navigation abilities were evaluated, followed by post-mortem semiquantitative tissue analyses. All animals in the Control, Lesion, Noradrenergic Transplant and Control CBL Transplant groups exhibited normal sensory-motor function and were equally efficient in the reference memory version of the water maze task. By contrast, working memory abilities were seen to be consistently impaired in the Lesion-only and Control CBL-Transplanted rats, which also exhibited a virtually complete noradrenergic fiber depletion and a significant 62-65% reduction in proliferating 5-bromo-2'deoxyuridine (BrdU)-positive progenitors in the dentate gyrus. Notably, the noradrenergic reinnervation promoted by the grafted LC, but not cerebellar neuroblasts, significantly ameliorated working memory performance and reinstated a fairly normal density of proliferating progenitors. Thus, LC-derived noradrenergic inputs may act as positive regulators of hippocampus-dependent spatial working memory possibly via the concurrent maintenance of normal progenitor proliferation in the dentate gyrus.

Acetylcholine and noradrenaline differentially regulate hippocampus-dependent spatial learning and memory.

Severe loss of cholinergic neurons in the basal forebrain nuclei and of noradrenergic neurons in the locus coeruleus are almost invariant histopathological hallmarks of Alzheimer's disease. However, the role of these transmitter systems in the spectrum of cognitive dysfunctions typical of the disease is still unclear, nor is it yet fully known whether do these systems interact and how. Selective ablation of either neuronal population, or both of them combined, were produced in developing animals to investigate their respective and/or concurrent contribution to spatial learning and memory, known to be severely affected in Alzheimer's disease. Single or double lesions were created in 4-8 days old rats by bilateral intraventricular infusion of two selective immunotoxins. At about 16 weeks of age, the animals underwent behavioural tests specifically designed to evaluate reference and working memory abilities, and their brains were later processed for quantitative morphological analyses. Animals with lesion to either system alone showed no significant reference memory deficits which, by contrast, were evident in the double-lesioned subjects. These animals could not adopt an efficient search strategy on a given testing day and were unable to transfer all relevant information to the next day, suggesting deficits in acquisition, storage and/or recall. Only animals with single noradrenergic or double lesions exhibited impaired working memory. Interestingly, ablation of cholinergic afferents to the hippocampus stimulated a robust ingrowth of thick fibres from the superior cervical ganglion which, however, did not appear to have contributed to the observed cognitive performance. Ascending cholinergic and noradrenergic afferents to the hippocampus and neocortex appear to be primarily involved in the regulation of different cognitive domains, but they may functionally interact, mainly at hippocampal level, for sustaining normal learning and memory. Moreover, these transmitter systems are likely to compensate for each other, but apparently not via ingrowing sympathetic fibres.

A Meta-Analysis Study of SOD1-Mutant Mouse Models of ALS to Analyse the Determinants of Disease Onset and Progression.

A complex interaction between genetic and external factors determines the development of amyotrophic lateral sclerosis (ALS). Epidemiological studies on large patient cohorts have suggested that ALS is a multi-step disease, as symptom onset occurs only after exposure to a sequence of risk factors. Although the exact nature of these determinants remains to be clarified, it seems clear that: (i) genetic mutations may be responsible for one or more of these steps; (ii) other risk factors are probably linked to environment and/or to lifestyle, and (iii) compensatory plastic changes taking place during the ALS etiopathogenesis probably affect the timing of onset and progression of disease. Current knowledge on ALS mechanisms and therapeutic targets, derives mainly from studies involving superoxide dismutase 1 (SOD1) transgenic mice; therefore, it would be fundamental to verify whether a multi-step disease concept can also be applied to these animal models. With this aim, a meta-analysis study has been performed using a collection of primary studies (n = 137), selected according to the following criteria: (1) the studies should employ SOD1 transgenic mice; (2) the studies should entail the presence of a disease-modifying experimental manipulation; (3) the studies should make use of Kaplan-Meier plots showing the distribution of symptom onset and lifespan. Then, using a subset of this study collection (n = 94), the effects of treatments on key molecular mechanisms, as well as on the onset and progression of disease have been analysed in a large population of mice. The results are consistent with a multi-step etiopathogenesis of disease in ALS mice (including two to six steps, depending on the particular SOD1 mutation), closely resembling that observed in patient cohorts, and revealed an interesting relationship between molecular mechanisms and disease manifestation. Thus, SOD1 mouse models may be considered of high predictive value to understand the determinants of disease onset and progression, as well as to identify targets for therapeutic interventions.

Clobetasol promotes neuromuscular plasticity in mice after motoneuronal loss via sonic hedgehog signaling, immunomodulation and metabolic rebalancing.

Motoneuronal loss is the main feature of amyotrophic lateral sclerosis, although pathogenesis is extremely complex involving both neural and muscle cells. In order to translationally engage the sonic hedgehog pathway, which is a promising target for neural regeneration, recent studies have reported on the neuroprotective effects of clobetasol, an FDA-approved glucocorticoid, able to activate this pathway via smoothened. Herein we sought to examine functional, cellular, and metabolic effects of clobetasol in a neurotoxic mouse model of spinal motoneuronal loss. We found that clobetasol reduces muscle denervation and motor impairments in part by restoring sonic hedgehog signaling and supporting spinal plasticity. These effects were coupled with reduced pro-inflammatory microglia and reactive astrogliosis, reduced muscle atrophy, and support of mitochondrial integrity and metabolism. Our results suggest that clobetasol stimulates a series of compensatory processes and therefore represents a translational approach for intractable denervating and neurodegenerative disorders.

Chronic α-Synuclein Accumulation in Rat Hippocampus Induces Lewy Bodies Formation and Specific Cognitive Impairments.

Occurrence of Lewy bodies (LBs)/Lewy neurites (LNs) containing misfolded fibrillar α-synuclein (α-syn) is one of the pathologic hallmarks of memory impairment-linked synucleinopathies, such as Parkinson's disease (PD) and dementia with LBs (DLB). While it has been shown that brainstem LBs may contribute to motor symptoms, the neuropathological substrates for cognitive symptoms are still elusive. Here, recombinant mouse α-syn fibrils were bilaterally injected in the hippocampus of female Sprague Dawley rats, which underwent behavioral testing for sensorimotor and spatial learning and memory abilities. No sensorimotor deficits affecting Morris water maze task performance were observed, nor was any reference memory disturbances detectable in injected animals. By contrast, significant impairments in working memory performance became evident at 12 months postinjection. These deficits were associated to a time-dependent increase in the levels of phosphorylated α-syn at Ser129 and in the stereologically estimated numbers of proteinase K (PK)-resistant α-syn aggregates within the hippocampus. Interestingly, pathologic α-syn aggregates were found in the entorhinal cortex and, by 12 months postinjection, also in the vertical limb of the diagonal band and the piriform cortices. No pathologic α-syn deposits were found within the substantia nigra (SN), the ventral tegmental area (VTA), or the striatum, nor was any loss of dopaminergic, noradrenergic, or cholinergic neurons detected in α-syn-injected animals, compared with controls. This would suggest that the behavioral impairments seen in the α-syn-injected animals might be determined by the long-term α-syn neuropathology, rather than by neurodegeneration per se, thus leading to the onset of working memory deficits.

Compensatory changes in degenerating spinal motoneurons sustain functional sparing in the SOD1-G93A mouse model of amyotrophic lateral sclerosis.

Plastic changes have been reported in the SOD1-G93A mouse model of amyotrophic lateral sclerosis, a disorder characterized by progressive motoneuronal loss; however, whether these changes related with the onset and development of motor impairments is still unclear. Here, the functional and anatomical changes taking place in SOD1-G93A mice and their time course were investigated during ongoing motoneuronal degeneration. Starting from about 4 postnatal weeks, SOD1-G93A and wild-type (WT) mice were evaluated in the rotarod test, to be sacrificed at about 12-13 or 19 weeks of age, and their lumbar spinal cords were processed for histo- and immunohistochemistry. Compared to age-matched WT controls, 12 weeks-old SOD1-G93A mice exhibited relatively mild or no motor impairments in the rotarod test, in spite of a dramatic (≈60%, as estimated by stereology) loss of choline acetyl-transferase (ChAT)-immunoreactive motoneurons which remained virtually unchanged in SOD1-G93A mice surviving up to 19 weeks. Notably, the functional sparing in SOD1-G93A mice at 12 weeks was paralleled by a marked ≈50% increase in motoneuron volume and a near-normal density of acetylcholinesterase-positive process arborization, which was significantly increased when analyzed as ratio to the decreased number of ChAT-positive motoneurons. By contrast, at 19 weeks, when motor deficits had become dramatically evident, both measures were found reverted to about 50-60% of control values. Thus, at specific stages during the progression of the disease, robust compensatory events take place in surviving motoneurons of SOD1-G93A mice, which sustain motor performance, and whose full understanding may highlight a valuable therapeutic opportunity window.

Clobetasol Modulates Adult Neural Stem Cell Growth via Canonical Hedgehog Pathway Activation.

Sonic hedgehog (Shh) signaling is a key pathway within the central nervous system (CNS), during both development and adulthood, and its activation via the 7-transmembrane protein Smoothened (Smo) may promote neuroprotection and restoration during neurodegenerative disorders. Shh signaling may also be activated by selected glucocorticoids such as clobetasol, fluocinonide and fluticasone, which therefore act as Smo agonists and hold potential utility for regenerative medicine. However, despite its potential role in neurodegenerative diseases, the impact of Smo-modulation induced by these glucocorticoids on adult neural stem cells (NSCs) and the underlying signaling mechanisms are not yet fully elucidated. The aim of the present study was to evaluate the effects of Smo agonists (i.e., purmorphamine) and antagonists (i.e., cyclopamine) as well as of glucocorticoids (i.e., clobetasol, fluocinonide and fluticasone) on NSCs in terms of proliferation and clonal expansion. Purmorphamine treatment significantly increased NSC proliferation and clonal expansion via GLI-Kruppel family member 1 (Gli1) nuclear translocation and such effects were prevented by cyclopamine co-treatment. Clobetasol treatment exhibited an equivalent pharmacological effect. Moreover, cellular thermal shift assay suggested that clobetasol induces the canonical Smo-dependent activation of Shh signaling, as confirmed by Gli1 nuclear translocation and also by cyclopamine co-treatment, which abolished these effects. Finally, fluocinonide and fluticasone as well as control glucocorticoids (i.e., prednisone, corticosterone and dexamethasone) showed no significant effects on NSCs proliferation and clonal expansion. In conclusion, our data suggest that Shh may represent a druggable target system to drive neuroprotection and promote restorative therapies.

Neuromuscular Plasticity in a Mouse Neurotoxic Model of Spinal Motoneuronal Loss.

Despite the relevant research efforts, the causes of amyotrophic lateral sclerosis (ALS) are still unknown and no effective cure is available. Many authors suggest that ALS is a multi-system disease caused by a network failure instead of a cell-autonomous pathology restricted to motoneurons. Although motoneuronal loss is the critical hallmark of ALS given their specific vulnerability, other cell populations, including muscle and glial cells, are involved in disease onset and progression, but unraveling their specific role and crosstalk requires further investigation. In particular, little is known about the plastic changes of the degenerating motor system. These spontaneous compensatory processes are unable to halt the disease progression, but their elucidation and possible use as a therapeutic target represents an important aim of ALS research. Genetic animal models of disease represent useful tools to validate proven hypotheses or to test potential therapies, and the conception of novel hypotheses about ALS causes or the study of pathogenic mechanisms may be advantaged by the use of relatively simple in vivo models recapitulating specific aspects of the disease, thus avoiding the inclusion of too many confounding factors in an experimental setting. Here, we used a neurotoxic model of spinal motoneuron depletion induced by injection of cholera toxin-B saporin in the gastrocnemius muscle to investigate the possible occurrence of compensatory changes in both the muscle and spinal cord. The results showed that, following the lesion, the skeletal muscle became atrophic and displayed electromyographic activity similar to that observed in ALS patients. Moreover, the changes in muscle fiber morphology were different from that observed in ALS models, thus suggesting that some muscular effects of disease may be primary effects instead of being simply caused by denervation. Notably, we found plastic changes in the surviving motoneurons that can produce a functional restoration probably similar to the compensatory changes occurring in disease. These changes could be at least partially driven by glutamatergic signaling, and astrocytes contacting the surviving motoneurons may support this process.

Noradrenergic Hypothesis Linking Neurodegeneration-Based Cognitive Decline and Astroglia.

In the past, manipulation of the cholinergic system was seen as the most likely therapeutic for neurodegeneration-based cognitive decline in Alzheimer's disease (AD) (Whitehouse et al., 1982). However, targeting the noradrenergic system also seems a promising strategy, since more recent studies revealed that in post-mortem tissue from patients with AD and other neurodegenerative disorders there is a robust correlation between cognitive decline and loss of neurons from the Locus coeruleus (LC), a system with diffuse noradrenaline (NA) innervation in the central nervous system (CNS). Therefore, the hypothesis has been considered that increasing NA signaling in the CNS will prevent, or at least halt the progression of neurodegeneration and cognitive decline. A hallmark of the age- and neurodegeneration-related cognitive decline is reduced neurogenesis. We here discuss noradrenergic dysfunction in AD-related cognitive decline in humans and its potential involvement in AD pathology and disease progression. We also focus on animal models to allow the validation of the noradrenergic hypothesis of AD, including those based upon the immunotoxin-mediated ablation of LC based on saporin, a protein synthesis interfering agent, which offers selective and graded demise of LC neurons, Finally, we address how astrocytes, an abundant and functionally heterogeneous cell type of neuroglia maintaining homeostasis, may participate in the regulation of neurogenesis, a new strategy for preventing LC neuron loss.

Essential role of hippocampal noradrenaline in the regulation of spatial working memory and TDP-43 tissue pathology.

Extensive loss of noradrenaline-containing neurons and fibers is a nearly invariant feature of Alzheimer's Disease (AD). However, the exact noradrenergic contribution to cognitive and histopathological changes in AD is still unclear. Here, this issue was addressed following selective lesioning and intrahippocampal implantation of embryonic noradrenergic progenitors in developing rats. Starting from about 3 months and up to 12 months post-surgery, animals underwent behavioral tests to evaluate sensory-motor, as well as spatial learning and memory, followed by post-mortem morphometric analyses. At 9 months, Control, Lesioned and Lesion + Transplant animals exhibited equally efficient sensory-motor and reference memory performance. Interestingly, working memory abilities were seen severely impaired in Lesion-only rats and fully recovered in Transplanted rats, and appeared partly lost again 2 months after ablation of the implanted neuroblasts. Morphological analyses confirmed the almost total lesion-induced noradrenergic neuronal and terminal fiber loss, the near-normal reinnervation of the hippocampus promoted by the transplants, and its complete removal by the second lesion. Notably, the noradrenergic-rich transplants normalized also the nuclear expression of the transactive response DNA-binding protein 43 (TDP-43) in various hippocampal subregions, whose cytoplasmic (i.e., pathological) occurrence appeared dramatically increased as a result of the lesions. Thus, integrity of ascending noradrenergic inputs to the hippocampus may be required for the regulation of specific aspects of learning and memory and to prevent TDP-43 tissue pathology.

Neuronal hemoglobin affects dopaminergic cells' response to stress.

Hemoglobin (Hb) is the major protein in erythrocytes and carries oxygen (O2) throughout the body. Recently, Hb has been found synthesized in atypical sites, including the brain. Hb is highly expressed in A9 dopaminergic (DA) neurons of the substantia nigra (SN), whose selective degeneration leads to Parkinson's disease (PD). Here we show that Hb confers DA cells' susceptibility to 1-methyl-4-phenylpyridinium (MPP+) and rotenone, neurochemical cellular models of PD. The toxic property of Hb does not depend on O2 binding and is associated with insoluble aggregate formation in the nucleolus. Neurochemical stress induces epigenetic modifications, nucleolar alterations and autophagy inhibition that depend on Hb expression. When adeno-associated viruses carrying α- and ß-chains of Hb are stereotaxically injected into mouse SN, Hb forms aggregates and causes motor learning impairment. These results position Hb as a potential player in DA cells' homeostasis and dysfunction in PD.

Selective noradrenaline depletion impairs working memory and hippocampal neurogenesis.

Noradrenergic neurons in the locus coeruleus play a role in learning and memory, and their loss is an early event in Alzheimer's disease pathogenesis. Moreover, noradrenaline may sustain hippocampal neurogenesis; however, whether are these events related is still unknown. Four to five weeks following the selective immunotoxic ablation of locus coeruleus neurons, young adult rats underwent reference and working memory tests, followed by postmortem quantitative morphological analyses to assess the extent of the lesion, as well as the effects on proliferation and/or survival of neural progenitors in the hippocampus. When tested in the Water Maze task, lesioned animals exhibited no reference memory deficit, whereas working memory abilities were seen significantly impaired, as compared with intact or sham-lesioned controls. Stereological analyses confirmed a dramatic noradrenergic neuron loss associated to reduced proliferation, but not survival or differentiation, of 5-bromo-2'deoxyuridine-positive progenitors in the dentate gyrus. Thus, ascending noradrenergic afferents may be involved in more complex aspects of cognitive performance (i.e., working memory) possibly via newly generated progenitors in the hippocampus.

Emx2 as a novel tool to suppress glioblastoma.

Glioblastoma is a devastating CNS tumour for which no cure is presently available. We wondered if manipulation of Emx2, which normally antagonizes cortico-cerebral astrogenesis by inhibiting proliferation of astrocyte progenitors, may be employed to counteract it. We found that Emx2 overexpression induced the collapse of seven out of seven in vitro tested glioblastoma cell lines. Moreover, it suppressed four out of four of these lines in vivo. As proven by dedicated rescue assays, the antioncogenic activity of Emx2 originated from its impact on at least six metabolic nodes, which accounts for the robustness of its effect. Finally, in two out of two tested lines, the tumor culture collapse was also achieved when Emx2 was driven by a neural stem cell-specific promoter, likely active within tumor-initiating cells. All that points to Emx2 as a novel, promising tool for therapy of glioblastoma and prevention of its recurrencies.

Effects of Pin1 Loss in Hdh(Q111) Knock-in Mice.

Huntington's disease (HD) is a fatal, dominantly inherited, neurodegenerative disorder due to a pathological expansion of the CAG repeat in the coding region of the HTT gene. In the quest for understanding the molecular basis of neurodegeneration, we have previously demonstrated that the prolyl isomerase Pin1 plays a crucial role in mediating p53-dependent apoptosis triggered by mutant huntingtin (mHtt) in vitro. To assess the effects of the lack of Pin1 in vivo, we have bred Pin1 knock-out mice with Hdh(Q111) knock-in mice, a genetically precise model of HD. We show that Pin1 genetic ablation modifies a portion of Hdh(Q111) phenotypes in a time-dependent fashion. As an early event, Pin1 activity reduces the DNA damage response (DDR). In midlife mice, by taking advantage of next-generation sequencing technology, we show that Pin1 activity modulates a portion of the alterations triggered by mHtt, extending the role of Pin1 to two additional Hdh(Q111) phenotypes: the unbalance in the "synthesis/concentration of hormones", as well as the alteration of "Wnt/ß-catenin signaling". In aging animals, Pin1 significantly increases the number of mHtt-positive nuclear inclusions while it reduces gliosis. In summary, this work provides further support for a role of Pin1 in HD pathogenesis.

Wharton's jelly derived mesenchymal stromal cells: Biological properties, induction of neuronal phenotype and current applications in neurodegeneration research.

Multipotent mesenchymal stromal cells, also known as mesenchymal stem cells (MSC), can be isolated from bone marrow or other tissues, including fat, muscle and umbilical cord. It has been shown that MSC behave in vitro as stem cells: they self-renew and are able to differentiate into mature cells typical of several mesenchymal tissues. Moreover, the differentiation toward non-mesenchymal cell lineages (e.g. neurons) has been reported as well. The clinical relevance of these cells is mainly related to their ability to spontaneously migrate to the site of inflammation/damage, to their safety profile thanks to their low immunogenicity and to their immunomodulation capacities. To date, MSCs isolated from the post-natal bone marrow have represented the most extensively studied population of adult MSCs, in view of their possible use in various therapeutical applications. However, the bone marrow-derived MSCs exhibit a series of limitations, mainly related to their problematic isolation, culturing and use. In recent years, umbilical cord (UC) matrix (i.e. Wharton's jelly, WJ) stromal cells have therefore emerged as a more suitable alternative source of MSCs, thanks to their primitive nature and the easy isolation without relevant ethical concerns. This review seeks to provide an overview of the main biological properties of WJ-derived MSCs. Moreover, the potential application of these cells for the treatment of some known dysfunctions in the central and peripheral nervous system will also be discussed.

Hippocampal Lewy pathology and cholinergic dysfunction are associated with dementia in Parkinson's disease.

The neuropathological substrate of dementia in patients with Parkinson's disease is still under debate, particularly in patients with insufficient alternate neuropathology for other degenerative dementias. In patients with pure Lewy body Parkinson's disease, previous post-mortem studies have shown that dopaminergic and cholinergic regulatory projection systems degenerate, but the exact pathways that may explain the development of dementia in patients with Parkinson's disease remain unclear. Studies in rodents suggest that both the mesocorticolimbic dopaminergic and septohippocampal cholinergic pathways may functionally interact to regulate certain aspects of cognition, however, whether such an interaction occurs in humans is still poorly understood. In this study, we performed stereological analyses of the A9 and A10 dopaminergic neurons and Ch1, Ch2 and Ch4 cholinergic neurons located in the basal forebrain, along with an assessment of α-synuclein pathology in these regions and in the hippocampus of six demented and five non-demented patients with Parkinson's disease and five age-matched control individuals with no signs of neurological disease. Moreover, we measured choline acetyltransferase activity in the hippocampus and frontal cortex of eight demented and eight non-demented patients with Parkinson's disease, as well as in the same areas of eight age-matched controls. All patients with Parkinson's disease exhibited a similar 80-85% loss of pigmented A9 dopaminergic neurons, whereas patients with Parkinson's disease dementia presented an additional loss in the lateral part of A10 dopaminergic neurons as well as Ch4 nucleus basalis neurons. In contrast, medial A10 dopaminergic neurons and Ch1 and Ch2 cholinergic septal neurons were largely spared. Despite variable Ch4 cell loss, cortical but not hippocampal cholinergic activity was consistently reduced in all patients with Parkinson's disease, suggesting significant dysfunction in cortical cholinergic pathways before frank neuronal degeneration. Patients with Parkinson's disease dementia were differentiated by a significant reduction in hippocampal cholinergic activity, by a significant loss of non-pigmented lateral A10 dopaminergic neurons and Ch4 cholinergic neurons (30 and 55% cell loss, respectively, compared with neuronal preservation in control subjects), and by an increase in the severity of α-synuclein pathology in the basal forebrain and hippocampus. Overall, these results point to increasing α-synuclein deposition and hippocampal dysfunction in a setting of more widespread degeneration of cortical dopaminergic and cholinergic pathways as contributing to the dementia occurring in patients with pure Parkinson's disease. Furthermore, our findings support the concept that α-synuclein deposition is associated with significant neuronal dysfunction in the absence of frank neuronal loss in Parkinson's disease.