The Cell and Molecular Biology of Neurodegenerative Diseases: An Overview

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Editorial: The next generation of tools and technologies for studying human neurons in a dish

Despite their prevalence, disorders of the brain, including neurodevelopmental, neurodegenerative, and other mental illnesses, have historically been some of the most challenging to treat. The enormous economic burden coupled with a paucity of curative therapies highlights an urgent need for new approaches and targets to tackle these diseases. One biologically relevant and transformative method that has been employed is the use of induced pluripotent stem cells (iPSCs) to generate neurons that closely mimic those found within the human brain (Mohamed et al., 2019). Advances in this area have enabled investigators to readily grow many of the cell types found within the human brain on a dish, increasing our understanding of mechanisms and targets that are implicated in these diseases and helping to facilitate translational efforts (Fermini et al., 2018)

Nanotherapeutic Modulation of Human Neural Cells and Glioblastoma in Organoids and Monocultures

Inflammatory processes in the brain are orchestrated by microglia and astrocytes in response to activators such as pathogen-associated molecular patterns, danger-associated molecular patterns and some nanostructures. Microglia are the primary immune responders in the brain and initiate responses amplified by astrocytes through intercellular signaling. Intercellular communication between neural cells can be studied in cerebral organoids, co-cultures or in vivo. We used human cerebral organoids and glioblastoma co-cultures to study glia modulation by dendritic polyglycerol sulfate (dPGS). dPGS is an extensively studied nanostructure with inherent anti-inflammatory properties. Under inflammatory conditions, lipocalin-2 levels in astrocytes are markedly increased and indirectly enhanced by soluble factors released from hyperactive microglia. dPGS is an effective anti-inflammatory modulator of these markers. Our results show that dPGS can enter neural cells in cerebral organoids and glial cells in monocultures in a time-dependent manner. dPGS markedly reduces lipocalin-2 abundance in the neural cells. Glioblastoma tumoroids of astrocytic origin respond to activated microglia with enhanced invasiveness, whereas conditioned media from dPGS-treated microglia reduce tumoroid invasiveness. Considering that many nanostructures have only been tested in cancer cells and rodent models, experiments in human 3D cerebral organoids and co-cultures are complementary in vitro models to evaluate nanotherapeutics in the pre-clinical setting. Thoroughly characterized organoids and standardized procedures for their preparation are prerequisites to gain information of translational value in nanomedicine. This study provides data for a well-characterized dendrimer (dPGS) that modulates the activation state of human microglia implicated in brain tumor invasiveness

Tektin 2 is required for central spindle microtubule organization and the completion of cytokinesis

During anaphase, the nonkinetochore microtubules in the spindle midzone become compacted into the central spindle, a structure which is required to both initiate and complete cytokinesis. We show that Tektin 2 (Tek2) associates with the spindle poles throughout mitosis, organizes the spindle midzone microtubules during anaphase, and assembles into the midbody matrix surrounding the compacted midzone microtubules during cytokinesis. Tek2 small interfering RNA (siRNA) disrupts central spindle organization and proper localization of MKLP1, PRC1, and Aurora B to the midzone and prevents the formation of a midbody matrix. Video microscopy revealed that loss of Tek2 results in binucleate cell formation by aberrant fusion of daughter cells after cytokinesis. Although a myosin II inhibitor, blebbistatin, prevents actin-myosin contractility, the microtubules of the central spindle are compacted. Strikingly, Tek2 siRNA abolishes this actin-myosin–independent midzone microtubule compaction. Thus, Tek2-dependent organization of the central spindle during anaphase is essential for proper midbody formation and the segregation of daughter cells after cytokinesis

Quantitative expansion microscopy for the characterization of the spectrin periodic skeleton of axons using fluorescence microscopy

Fluorescent nanoscopy approaches have been used to characterize the periodic organization of actin,spectrin and associated proteins in neuronal axons and dendrites. This membrane-associated periodicskeleton (MPS) is conserved across animals, suggesting it is a fundamental component of neuronalextensions. The nanoscale architecture of the arrangement (190 nm) is below the resolution limitof conventional fluorescent microscopy. Fluorescent nanoscopy, on the other hand, requires costlyequipment and special analysis routines, which remain inaccessible to most research groups. Thisreport aims to resolve this issue by using protein-retention expansion microscopy (pro-ExM) to revealthe MPS of axons. ExM uses reagents and equipment that are readily accessible in most neurobiologylaboratories. We first explore means to accurately estimate the expansion factors of protein structureswithin cells. We then describe the protocol that produces an expanded specimen that can be examinedwith any fluorescent microscopy allowing quantitative nanoscale characterization of the MPS. Wevalidate ExM results by direct comparison to stimulated emission depletion (STED) nanoscopy. Weconclude that ExM facilitates three-dimensional, multicolor and quantitative characterization of theMPS using accessible reagents and conventional fluorescent microscopes.Fil: Martínez, Gaby F.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Gazal, Nahir Guadalupe. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Quassollo Infanzon, Gonzalo Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Szalai, Alan Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Del Cid Pellitero, Esther. No especifíca;Fil: Durcan, Thomas M.. No especifíca;Fil: Fon, Edward A.. No especifíca;Fil: Bisbal, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Stefani, Fernando Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Unsain, Nicolas. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentin

Mild cognitive impairment with Lewy bodies: neuropsychiatric supportive symptoms and cognitive profile

This is the author accepted manuscript. The final version is available from Cambridge University Press via the DOI in this recordBackground Recently published diagnostic criteria for mild cognitive impairment with Lewy bodies (MCI-LB) include five neuropsychiatric supportive features (non-visual hallucinations, systematised delusions, apathy, anxiety and depression). We have previously demonstrated that the presence of two or more of these symptoms differentiates MCI-LB from MCI due to Alzheimer’s disease (MCI-AD) with a likelihood ratio >4. The aim of this study was to replicate the findings in an independent cohort. Methods Participants ≥60 years old with MCI were recruited. Each participant had a detailed clinical, cognitive and imaging assessment including FP-CIT SPECT and cardiac MIBG. The presence of neuropsychiatric supportive symptoms was determined using the neuropsychiatric inventory (NPI). Participants were classified as MCI-AD, possible MCI-LB and probable MCI-LB based on current diagnostic criteria. Participants with possible MCI-LB were excluded from further analysis. Results Probable MCI-LB (n=28) had higher NPI total and distress scores than MCI-AD (n=30). 59% of MCI-LB had two or more neuropsychiatric supportive symptoms compared with 9% of MCI-AD (likelihood ratio 6.5, p<0.001). MCI-LB participants also had significantly greater delayed recall and a lower Trails A:Trails B ratio than MCI-AD. Conclusions 5 MCI-LB is associated with significantly greater neuropsychiatric symptoms than MCI-AD. The presence of two or more neuropsychiatric supportive symptoms as defined by MCI-LB diagnostic criteria is highly specific and moderately sensitive for a diagnosis of MCI-LB. The cognitive profile of MCI-LB differs from MCI-AD, with greater executive and lesser memory impairment, but these differences are not sufficient to differentiate MCI-LB from MCI-AD.Alzheimer’s Research UKNational Institute for Health Research (NIHR

Identifying parkinsonism in mild cognitive impairment.

Introduction Clinical parkinsonism is a core diagnostic feature for mild cognitive impairment with Lewy bodies (MCI-LB) but can be challenging to identify. A five-item scale derived from the Unified Parkinson’s Disease Rating Scale (UPDRS) has been recommended for the assessment of parkinsonism in dementia. This study aimed to determine whether the five-item scale is effective to identify parkinsonism in MCI. Methods Participants with MCI from two cohorts (n=146) had a physical examination including the UPDRS and [123I]-FP-CIT SPECT striatal dopaminergic imaging. Participants were classified as having clinical parkinsonism (P+) or no parkinsonism (P-), and with abnormal striatal dopaminergic imaging (D+) or normal imaging (D-). The five-item scale was the sum of UPDRS tremor at rest, bradykinesia, action tremor, facial expression, and rigidity scores. The ability of the scale to differentiate P+D+ and P-D- participants was examined. Results The five-item scale had an AUROC of 0.92 in Cohort 1, but the 7/8 cut-off defined for dementia had low sensitivity to identify P+D+ participants (sensitivity 25%, specificity 100%). Optimal sensitivity and specificity was obtained at a 3/4 cut-off (sensitivity 83%, specificity 88%). In Cohort 2, the five-item scale had an AUROC of 0.97, and the 3/4 cut-off derived from Cohort 1 showed sensitivity of 100% and a specificity of 82% to differentiate P+D+ from P-D- participants. The five-item scale was not effective in differentiating D+ from D- participants. Conclusions The five-item scale is effective to identify parkinsonism in MCI, but a lower threshold must be used in MCI compared with dementia

Olfactory impairment in mild cognitive impairment with Lewy bodies and Alzheimer’s disease

This is the author accepted manuscript. The final version is available from Cambridge University Press via the DOI in this recordObjectives: Impaired olfaction may be a biomarker for early Lewy body disease but its value in Mild Cognitive Impairment with Lewy bodies (MCI-LB) is unknown. We compared olfaction in MCI-LB with MCI due to Alzheimer’s disease (MCI-AD) and healthy older adults. We hypothesised that olfactory function would be worse in probable MCI-LB than in both MCI- AD and healthy comparison subjects (HC). Design: Cross-sectional study assessing olfaction using Sniffin’ Sticks 16 (SS-16) in MCI-LB, MCI- AD and HC with longitudinal follow-up. Differences were adjusted for age and receiver operating characteristic curves were used for discriminating MCI-LB from MCI-AD andHC. Setting: Participants were recruited from Memory Services in the North East of England Participants: 38 probable MCI-LB, 33 MCI-AD, 19 possible MCI-LB and 32HC. Measurements: Olfaction was assessed using SS-16 and a questionnaire. Results: Participants with probable MCI-LB had worse olfaction than both MCI-AD (Age-adjusted mean difference (B)=2.05,95% CI:0.62-3.49, p=.005) and HC (B=3.96, 95% CI:2.51–5.40, p<.001). The previously-identified cut-off score for the SS-16 of ≤ 10 had 84% sensitivity for probable MCI-LB (95% CI: 69-94%) but 30% specificity vs MCI-AD. ROC analysis found a lower cut-off of ≤ 7 was better (63% sensitivity for MCI-LB, with 73% specificity vs MCI-AD and 97% vsHC). Asking about olfactory impairments was not useful in identifying them. Conclusions: MCI-LB had worse olfaction than MCI-AD and normal ageing. A lower cut-off score of ≤ 7 is required when using SS-16 in such patients. Olfactory testing may have value in identifying early LB disease in memory services.Alzheimer’s Research UKNational Institute for Health Research (NIHR