177,009 research outputs found
Dendritic spines in alzheimer’s disease : How the actin cytoskeleton contributes to synaptic failure
No full textAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by Aβ-driven synaptic dysfunction in the early phases of pathogenesis. In the synaptic context, the actin cytoskeleton is a crucial element to maintain the dendritic spine architecture and to orchestrate the spine’s morphology remodeling driven by synaptic activity. Indeed, spine shape and synaptic strength are strictly correlated and precisely governed during plasticity phenomena in order to convert short-term alterations of synaptic strength into long-lasting changes that are embedded in stable structural modification. These functional and structural modifications are considered the biological basis of learning and memory processes. In this review we discussed the existing evidence regarding the role of the spine actin cytoskeleton in AD synaptic failure. We revised the physiological function of the actin cytoskeleton in the spine shaping and the contribution of actin dynamics in the endocytosis mechanism. The internalization process is implicated in different aspects of AD since it controls both glutamate receptor membrane levels and amyloid generation. The detailed understanding of the mechanisms controlling the actin cytoskeleton in a unique biological context as the dendritic spine could pave the way to the development of innovative synapse-tailored therapeutic interventions and to the identification of novel biomarkers to monitor synaptic loss in AD
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
Looking at Alzheimer’s disease pathogenesis from the nuclear side
No full textAlzheimer’s disease (AD) is a neurodegenerative disorder representing the most common form of dementia. It is biologically characterized by the deposition of extracellular amyloid‐β (Aβ) senile plaques and intracellular neurofibrillary tangles, constituted by hyperphosphorylated tau protein. The key protein in AD pathogenesis is the amyloid precursor protein (APP), which is cleaved by secretases to produce several metabolites, including Aβ and APP intracellular domain (AICD). The greatest genetic risk factor associated with AD is represented by the Apolipoprotein E ε4 (APOE ε4) allele. Importantly, all of the above‐mentioned molecules that are strictly related to AD pathogenesis have also been described as playing roles in the cell nucleus. Accordingly, evidence suggests that nuclear functions are compromised in AD. Furthermore, modulation of transcription maintains cellular homeostasis, and alterations in transcriptomic profiles have been found in neurodegenerative diseases. This report reviews recent advancements in the AD players‐mediated gene expression. Aβ, tau, AICD, and APOE ε4 localize in the nucleus and regulate the transcription of several genes, part of which is involved in AD pathogenesis, thus suggesting that targeting nuclear functions might provide new therapeutic tools for the disease
Nonlinear mixed-effects models to analyze actin dynamics in dendritic spines
No full textAbstract 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
Appropriate Similarity Measures for Author Cocitation Analysis
No full textWe 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
"Closing the R&D Gap, Evaluating the Sources of R&D Spending"
No full textBoth spending and tax policies have been implemented in the United States with the goal of stimulating private sector research and development (R&D). Karier questions whether current R&D policy, especially the research and experimentation tax credit, can contribute to closing the gap between nondefense expenditures on R&D in the United States and such expenditures in other countries, such as Japan and Germany. He also explores possible changes to our current R&D policy to make it more effective.
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe 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
Letter from R. R. Zellick, Assistant Trust Officer, Anglo California National Bank of San Francisco, to Joseph R. Goodman, October 2, 1942
No full textLetter from R. R. Zellick, Assistant Trust Officer at The Anglo California National Bank of San Francisco, to Joseph R. Goodman, regarding property owned by Dave Tatsuno. Zellick mentions a dispute between current tenants and Tatsuno, and that Tatsuno has asked Goodman to help locate trustworthy tenants.Personal correspondence, organizational records, government documents, publications, and other papers created or collected by Joseph R. Goodman documenting the forced removal and incarceration of Japanese Americans during World War II, as well as organized resistance to incarceration. Included in the collection are records of the Japanese Young Men's Christian Association and the Japanese American Citizens' League in San Francisco, including papers of the Japanese YMCA's executive secretary Lincoln Kanai; Sakai family papers; Goodman's correspondence to and from Japanese American incarcerees, organizations opposing forced removal and incarceration of Japanese Americans, the War Relocation Authority, and others; publications, photographs, and ephemera from the Topaz Relocation Center, where Goodman taught high school; War Relocation Authority records and publications; and newspaper clippings, pamphlets, and reports about forced removal and incarceration created by various government, religious, and civic organizations, in California and nationwide
Dispelling the Myths Behind First-author Citation Counts
No full textWe 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
Liftings for noncomplete probability spaces
No full textThe current state of knowledge concerning liftings for noncomplete probability spaces is discussed. This is a somewhat expanded version of the author's talk given at the 1991 Summer Conference on General Topology and Applications in Honor of Mary Ellen Rudin and Her Work.PT: S; CR: BURKE MR, IN PRESS P AM MATH S BURKE MR, 1991, ISRAEL J MATH, V73, P33 BURKE MR, 1992, ISRAEL J MATH, V79, P289 CARLSON T, THEOREM LIFTING CHRISTENSEN JPR, 1974, TOPOLOGY BOREL STRUC FREMLIN DH, 1989, HDB BOOLEAN ALGEBRAS, P877 INOESCUTULCEA A, 1966, 5TH P BERK S MATH ST, V2 IONESCUTULCEA A, 1967, CONTRIBUTIONS PROB 1, P63 IONESCUTULCEA A, 1969, TOPICS THEORY LIFTIN JECH TJ, 1978, SET THEORY JOHNSON RA, 1980, P AM MATH SOC, V80, P234 JUST W, IN PRESS T AM MATH S KUPKA J, 1983, INDIANA U MATH J, V32, P717 LOSERT V, 1983, LNM, V1080, P95 MAHARAM D, 1958, P AM MATH SOC, V9, P987 SHELAH S, 1983, ISRAEL J MATH, V45, P90 TALAGRAND M, 1982, P AM MATH SOC, V84, P379 VONNEUMANN J, 1931, CRELLES J MATH, V165, P109; NR: 18; TC: 0; J9: ANN N Y ACAD SCI; PG: 4; GA: BZ86BSource type: Electronic(1
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