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THE ROLE OF ACTIN CYTOSKELETON IN REGULATING NEURONAL FUNCTION IN PHYSIOLOGY AND DISEASE: ZOOM IN ON THE CYCLASE-ASSOCIATED PROTEIN 2
No full textLa malattia di Alzheimer (AD) è una patologia neurodegenerativa progressiva caratterizzata dalla
deposizione di placche extracellulari di beta amiloide (Aβ) e dall'accumulo intracellulare di proteina tau
iperfosforilata. Recenti studi indicano la perdita di sinapsi come il più significativo indicatore del declino
cognitivo nell'AD, portando alla classificazione dell'AD come “sinaptopatia”. Il citoscheletro di actina
svolge un ruolo critico nella plasticità sinaptica e le alterazioni delle dinamiche di actina contribuiscono
al deterioramento sinaptico nell'AD. Il mio progetto si è focalizzato sul ruolo della proteina Cyclase
associated protein 2 (CAP2), un modulatore dell'actina essenziale per l'architettura delle spine e la
trasmissione sinaptica e che risulta alterato nei pazienti con AD. In effetti, l'espressione di CAP2 è
ridotta nell'AD e, di conseguenza, i livelli sinaptici della forma dimerica di CAP2 sono ridotti, alterando
quindi l'associazione di cofilin con il dimero/monomero di CAP2. Inoltre, l'actina e le proteine ad essa
associate regolano la dinamica mitocondriale, per cui la disfunzione del citoscheletro di actina può
contribuire ulteriormente alla patologia dell'AD, aggiungendo un altro livello di complessità alla
malattia.
In questa tesi abbiamo riportato che i pazienti affetti da AD presentano livelli di CAP2 nel liquor più
elevati rispetto ai controlli e ai pazienti affetti da altre patologie neurodegenerative, che correlano
positivamente con la tau totale e la tau fosforilata in Thr181 (p-tau181). I livelli di mRNA di CAP2 sono
ridotti nell'ippocampo dei pazienti con AD. Pertanto, per evidenziare un potenziale legame biologico tra
CAP2 e tau, abbiamo ridotto l'espressione di CAP2 nei neuroni ippocampali e abbiamo misurato un
aumento significativo di p-tau181 e un concomitante aumento dell'attivazione della caspasi-3, senza
influire sulla vitalità cellulare. Inoltre, abbiamo dimostrato una maggiore variabilità, che suggerisce una
maggiore instabilità, del citoscheletro di actina delle spine dendritiche in seguito al silenziamento di
CAP2.
Inoltre, abbiamo dimostrato il coinvolgimento di CAP2 nei meccanismi rilevanti per la dinamica
mitocondriale actina-dipendente. Infatti, la delezione di CAP2 innesca un'evidente alterazione della
morfologia mitocondriale, mediata dalla inibizione delle dinamiche di fissione Drp1-dipendenti, e una
contemporanea perdita di massa mitocondriale causata da alterazioni nei processi di biogenesi.
Data la ridotta espressione di CAP2 nell'AD, abbiamo verificato gli effetti di un'aumentata espressione
di CAP2 nei topi AD e abbiamo osservato che questo approccio ripristina le vie sinaptiche mediate dal
complesso CAP2/cofilin e le vie di plasticità sinaptica, preservando così la funzione cognitiva.
L’overespressione di CAP2 riduce la formazione di cofilin-actin rods e attenua le anomalie della proteina
tau. CAP2 si accumula all'interno dei cofilin-actin rods specificamente indotti dagli oligomeri di Aβ.
Inoltre, la dimerizzazione di CAP2 è necessaria per prevenire la perdita di sinapsi indotta da Aβ, ma non
per proteggere i neuroni dalla formazione degli actin rods.
Nel complesso, questi risultati rafforzano il ruolo della disfunzione sinaptica nelle prime fasi dell'AD e
supportano la correlazione del deterioramento sinaptico dell'AD con le alterazioni del citoscheletro di
actina, evidenziando che CAP2 si trova al crocevia di molteplici vie biologiche alla base della patogenesi
dell'AD.Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the deposition
of extracellular amyloid-beta (Aβ) plaques and intracellular accumulation of hyperphosphorylated tau
protein. Recent studies point out synaptic loss as the strongest indicator of cognitive impairment in AD,
leading to the classification of AD as a “synaptopathy”. The actin cytoskeleton plays a critical role in
synaptic plasticity, and disruptions in actin dynamics contribute to synaptic failure in AD. We focused
on cyclase-associated protein 2 (CAP2), an actin-modifier essential for spine architecture and synaptic
transmission and altered in AD patients. Indeed, CAP2 expression is reduced in AD and, thereby, the
synaptic availability of CAP2 dimer is decreased, having an impact of cofilin association with the CAP2
dimer/monomer. Additionally, actin and its associated proteins regulate mitochondrial dynamics,
therefore actin cytoskeleton dysfunction may further contribute to AD pathology, adding another layer
of complexity to the disease pathology.
Here, we reported that AD patients show higher CAP2 CSF levels compared to controls and non-AD
patients, that positively correlate with total and tau phosphorylated at Thr181 (p-tau181). CAP2 mRNA
levels are reduced in the hippocampus of AD patients. Therefore, to assess a potential biological link
between CAP2 and tau, we downregulated CAP2 expression in hippocampal neurons and we measured
a significant increase in p-tau181 and a concomitant increase of caspase-3 activation without affecting
cell viability. In addition, we demonstrated a higher variance, suggesting increased instability, of
dendritic spine actin cytoskeleton upon CAP2 down-regulation.
Moreover, we show the involvement of CAP2 in those mechanisms relevant for actin-dependent
mitochondrial dynamics. Indeed, the ablation of CAP2 triggers an evident alteration of mitochondrial
morphology, mediated by the suppression of Drp1-dependent fission dynamics, and a simultaneous
loss of mitochondrial mass caused by alterations in mitobiogenesis processes.
Given the downregulation of CAP2 in AD, we described that CAP2 gene delivery in AD mice restores
synaptic CAP2/cofilin and plasticity pathways, thus preserving cognitive function. CAP2 overexpression
reduces cofilin actin rods formation and mitigates tau abnormalities. CAP2 is accumulated within
cofilin-actin rods specifically induced by Aβ oligomers. Furthermore, CAP2 dimerization is required for
preventing Aβ-induced synaptic loss but not to protect neurons from cofilin-actin rods formation.
Taken together, these findings strengthen the role of synaptic pathology in the early stages of AD and
support the correlation of AD synaptic failure with actin cytoskeleton dysfunction, highlighting CAP2 at
the crossroad of multiple pathways underlying AD pathogenesis
Nonlinear mixed-effects models to analyze actin dynamics in dendritic spines
Get PDFAbstract Fluorescence recovery after photobleaching (FRAP) allows to study actin-turnover in dendritic spines by providing recovery trajectories over time within a nested data structure (i.e. spine/neuron/culture). Statistical approaches to FRAP usually consider one-phase association models to estimate recovery-curve-specific parameters and test statistical hypotheses on curve parameters either at the spine or neuron level, ignoring the nested data structure. However, this approach leads to pseudoreplication concerns. We propose a nonlinear mixed-effects model to integrate the one-phase association model estimate with the nested data structure of FRAP experiments; this also allows us to model heteroscedasticity and time dependence in the data. We used this approach to evaluate the effect of the downregulation of the actin-binding protein CAP2 on actin dynamics. Our model allows the additional modelling of the variance function across experimental conditions, which may represent a novel parameter of interest in FRAP experiments. Indeed, the detected differential effect of the experimental condition on the variance component captures the increased instability of time-specific observations around the spine-specific trajectory for the CAP2-downregulated spines compared to the control spines. We hypothesise that this parameter reflects the increased instability of the actin cytoskeleton in dendritic spines upon CAP2 downregulation. We developed an R-based Shiny application, termed FRApp, to fit the statistical models introduced without requiring programming expertise
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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