Liposomes for Targeted Delivery of Active Agents against Neurodegenerative Diseases (Alzheimer's Disease and Parkinson's Disease)

Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease represent a huge unmet medical need. The prevalence of both diseases is increasing, but the efficacy of treatment is still very limited due to various factors including the blood brain barrier (BBB). Drug delivery to the brain remains the major challenge for the treatment of all neurodegenerative diseases because of the numerous protective barriers surrounding the central nervous system. New therapeutic drugs that cross the BBB are critically needed for treatment of many brain diseases. One of the significant factors on neurotherapeutics is the constraint of the blood brain barrier and the drug release kinetics that cause peripheral serious side effects. Contrary to common belief, neurodegenerative and neurological diseases may be multisystemic in nature, and this presents numerous difficulties for their potential treatment. Overall, the aim of this paper is to summarize the last findings and news related to liposome technology in the treatment of neurodegenerative diseases and demonstrate the potential of this technology for the development of novel therapeutics and the possible applications of liposomes in the two most widespread neurodegenerative diseases, Alzheimer's disease and Parkinson's disease

Loss of GABAergic cortical neurons underlies the neuropathology of Lafora disease

BACKGROUND: Lafora disease is an autosomal recessive form of progressive myoclonic epilepsy caused by defects in the EPM2A and EPM2B genes. Primary symptoms of the pathology include seizures, ataxia, myoclonus, and progressive development of severe dementia. Lafora disease can be caused by defects in the EPM2A gene, which encodes the laforin protein phosphatase, or in the NHLRC1 gene (also called EPM2B) codifying the malin E3 ubiquitin ligase. Studies on cellular models showed that laforin and malin interact and operate as a functional complex apparently regulating cellular functions such as glycogen metabolism, cellular stress response, and the proteolytic processes. However, the pathogenesis and the molecular mechanism of the disease, which imply either laforin or malin are poorly understood. Thus, the aim of our study is to elucidate the molecular mechanism of the pathology by characterizing cerebral cortex neurodegeneration in the well accepted murine model of Lafora disease EPM2A-/- mouse. RESULTS: In this article, we want to asses the primary cause of the neurodegeneration in Lafora disease by studying GABAergic neurons in the cerebral cortex. We showed that the majority of Lafora bodies are specifically located in GABAergic neurons of the cerebral cortex of 3 months-old EPM2A-/- mice. Moreover, GABAergic neurons in the cerebral cortex of younger mice (1 month-old) are decreased in number and present altered neurotrophins and p75NTR signalling. CONCLUSIONS: Here, we concluded that there is impairment in GABAergic neurons neurodevelopment in the cerebral cortex, which occurs prior to the formation of Lafora bodies in the cytoplasm. The dysregulation of cerebral cortex development may contribute to Lafora disease pathogenesis

Gelsolin Restores Aβ-Induced Alterations in Choroid Plexus Epithelium

Histologically, Alzheimer's disease (AD) is characterized by senile plaques and cerebrovascular amyloid deposits. In previous studies we demonstrated that in AD patients, amyloid-β (Aβ) peptide also accumulates in choroid plexus, and that this process is associated with mitochondrial dysfunction and epithelial cell death. However, the molecular mechanisms underlying Aβ accumulation at the choroid plexus epithelium remain unclear. Aβ clearance, from the brain to the blood, involves Aβ carrier proteins that bind to megalin, including gelsolin, a protein produced specifically by the choroid plexus epithelial cells. In this study, we show that treatment with gelsolin reduces Aβ-induced cytoskeletal disruption of blood-cerebrospinal fluid (CSF) barrier at the choroid plexus. Additionally, our results demonstrate that gelsolin plays an important role in decreasing Aβ-induced cytotoxicity by inhibiting nitric oxide production and apoptotic mitochondrial changes. Taken together, these findings make gelsolin an appealing tool for the prophylactic treatment of AD

Cognitive frailty: an update

This review article provides an update of the empirical research on cognitive fragility conducted in the last four years. The studies retrieved were classified in four different categories. The first category includes articles relating cognitive frailty to cognitive reserve and which continue to highlight the importance of educational level. The second category includes recent research on cognitive fragility biomarkers, involving neuroimaging, metabolism and, in a novel way, microbiota. The third category includes research on how cognitive frailty is related to motor development and physical functioning, exploring e.g. the use of technology to study motor markers of cognitive frailty. Finally, in the fourth category, research clarifying the difference between reversible frailty and potentially reversible cognitive frailty has led to new interventions aimed at reducing cognitive frailty and preventing negative health outcomes. Interventions based on physical activity and multicomponent interventions are particularly emphasized. In addition, recent research explores the long-term effects of dual interventions in older adults living in nursing homes. In summary, research on cognitive frailty has increased in recent years, and applied aspects have gained importanceThis work was financially supported through FEDER founds (A way to make Europe) by the Spanish AEI (doi: 10.13039/501100011033; Refs. PID2020-114521RB-C21 and PSI2017-89389-C2-1-R) and by the Galician Government (Consellería de Cultura, Educación e Ordenación Universitaria; GI-1807-USC: Ref. ED431C 2021/04). CB was supported by a Research Initiation Grant from the University of Santiago de Compostela, co-financed by Banco Santander. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publicationS

Mania as Debut of Cushing's Syndrome

This is a case of a patient affected by Cushing syndrome that was admitted at the hospital due to hormonal problems. He had presented psychiatric symptoms that were mistakenly considered not directly connected to the pathology causing the clinical condition, but a mere psychological reaction to it

Annexin A5 prevents amyloid-β-induced toxicity in choroid plexus: implication for Alzheimer’s disease

In Alzheimer's disease (AD) amyloid-beta (A beta) deposits may cause impairments in choroid plexus, a specialised brain structure which forms the blood-cerebrospinal fluid (CSF) barrier. We previously carried out a mass proteomic-based study in choroid plexus from AD patients and we found several differentially regulated proteins compared with healthy subjects. One of these proteins, annexin A5, was previously demonstrated implicated in blocking A beta -induced cytotoxicity in neuronal cell cultures. Here, we investigated the effects of annexin A5 on A beta toxicity in choroid plexus. We used choroid plexus tissue samples and CSF from mild cognitive impairment (MCI) and AD patients to analyse A beta accumulation, cell death and annexin A5 levels compared with control subjects. Choroid plexus cell cultures from rats were used to analyse annexin A5 effects on A beta -induced cytotoxicity. AD choroid plexus exhibited progressive reduction of annexin A5 levels along with progressive increased A beta accumulation and cell death as disease stage was higher. On the other hand, annexin A5 levels in CSF from patients were found progressively increased as the disease stage increased in severity. In choroid plexus primary cultures, A beta administration reduced endogenous annexin A5 levels in a time-course dependent manner and simultaneously increased annexin A5 levels in extracellular medium. Annexin A5 addition to choroid plexus cell cultures restored the A beta -induced impairments on autophagy flux and apoptosis in a calcium-dependent manner. We propose that annexin A5 would exert a protective role in choroid plexus and this protection is lost as A beta accumulates with the disease progression. Then, brain protection against further toxic insults would be jeopardised

Plasma β-III tubulin, neurofilament light chain and glial fibrillary acidic protein are associated with neurodegeneration and progression in schizophrenia

Schizophrenia is a progressive disorder characterized by multiple psychotic relapses. After every relapse, patients may not fully recover, and this may lead to a progressive loss of functionality. Pharmacological treatment represents a key factor to minimize the biological, psychological and psychosocial impact of the disorder. The number of relapses and the duration of psychotic episodes induce a potential neuronal damage and subsequently, neurodegenerative processes. Thus, a comparative study was performed, including forty healthy controls and forty-two SZ patients divided into first-episode psychosis (FEP) and chronic SZ (CSZ) subgroups, where the CSZ sub group was subdivided by antipsychotic treatment. In order to measure the potential neuronal damage, plasma levels of β-III tubulin, neurofilament light chain (Nf-L), and glial fibrillary acidic protein (GFAP) were performed. The results revealed that the levels of these proteins were increased in the SZ group compared to the control group (P < 0.05). Moreover, multiple comparison analysis showed highly significant levels of β-III tubulin (P = 0.0002), Nf-L (P = 0.0403) and GFAP (P < 0.015) in the subgroup of CSZ clozapine-treated. In conclusion, β-III tubulin, Nf-L and GFAP proteins may be potential biomarkers of neurodegeneration and progression in SZFundação para a Ciência e a Tecnologia | Ref. SFRH/BD/135623/20Instituto de Salud Carlos III | Ref. P16/00405Ministerio de Sanidad, Igualdad y Política Social | Ref. 2017I054Agencia del Conocimiento en Salud | Ref. PRIS2-17Xunta de Galicia | Ref. IN607C-2017/02Xunta de Galicia | Ref. IN607B 2018/1

Acute aquatic toxicity to zebrafish and bioaccumulation in marine mussels of antimony tin oxide nanoparticles

Antimony tin oxide (Sb2O5/SnO2) is effective in the absorption of infrared radiation for applications, such as skylights. As a nanoparticle (NP), it can be incorporated into films or sheets providing infrared radiation attenuation while allowing for a transparent final product. The acute toxicity exerted by commercial Sb2O5/SnO2 (ATO) NPs was studied in adults and embryos of zebrafish (Danio rerio). Our results suggest that these NPs do not induce an acute toxicity in zebrafish, either adults or embryos. However, some sub-lethal parameters were altered: heart rate and spontaneous movements. Finally, the possible bioaccumulation of these NPs in the aquacultured marine mussel Mytilus sp. was studied. A quantitative analysis was performed using single particle inductively coupled plasma mass spectrometry (sp-ICP-MS). The results indicated that, despite being scarce (2.31 × 106 ± 9.05 × 105 NPs/g), there is some accumulation of the ATO NPs in the mussel. In conclusion, commercial ATO NPs seem to be quite innocuous to aquatic organisms; however, the fact that some of the developmental parameters in zebrafish embryos are altered should be considered for further investigation. More in-depth analysis of these NPs transformations in the digestive tract of humans is needed to assess whether their accumulation in mussels presents an actual risk to humans.Fundação para a Ciência e Tecnologia | Ref. 2020.04021.CEECIN

Plasma?-III tubulin, neurofilament light chain and glial fibrillary acidic protein are associated with neurodegeneration and progression in schizophrenia

Schizophrenia is a progressive disorder characterized by multiple psychotic relapses. After every relapse, patients may not fully recover, and this may lead to a progressive loss of functionality. Pharmacological treatment represents a key factor to minimize the biological, psychological and psychosocial impact of the disorder. The number of relapses and the duration of psychotic episodes induce a potential neuronal damage and subsequently, neurodegenerative processes. Thus, a comparative study was performed, including forty healthy controls and forty-two SZ patients divided into first-episode psychosis (FEP) and chronic SZ (CSZ) subgroups, where the CSZ sub group was subdivided by antipsychotic treatment. In order to measure the potential neuronal damage, plasma levels of beta-III tubulin, neurofilament light chain (Nf-L), and glial fibrillary acidic protein (GFAP) were performed. The results revealed that the levels of these proteins were increased in the SZ group compared to the control group (P < 0.05). Moreover, multiple comparison analysis showed highly significant levels of beta-III tubulin (P = 0.0002), Nf-L (P = 0.0403) and GFAP (P < 0.015) in the subgroup of CSZ clozapine-treated. In conclusion, beta-III tubulin, Nf-L and GFAP proteins may be potential biomarkers of neurodegeneration and progression in SZ