p25/Cdk5-mediated retinoblastoma phosphorylation is an early event in neuronal cell death

In large models of neuronal cell death, there is a tight correlation between Cdk5 deregulation and cell-cycle dysfunction. However, pathways that link Cdk5 to the cell cycle during neuronal death are still unclear. We have investigated the molecular events that precede p25/Cdk5-triggered neuronal death using a neuronal cell line that allows inducible p25 expression. In this system, no sign of apoptosis was seen before 24 hours of p25 induction. Thus, at that time, cell-cycle-regulatory proteins were analysed by immunoblotting and some of them showed a significant deregulation. Interestingly, after time-course experiments, the earliest feature correlated with p25 expression was the phosphorylation of the retinoblastoma protein (Rb). Indeed, this phosphorylation was observed 6 hours after p25 induction and was abolished in the presence of a Cdk5 inhibitor, roscovitine, which does not inhibit the usual Rb cyclin-D kinases Cdk4 and Cdk6. Furthermore, analyses of levels and subcellular localization of Cdk-related cyclins did not reveal any change following Cdk5 activation, arguing for a direct effect of Cdk5 activity on Rb protein. This latter result was clearly demonstrated by in vitro kinase assays showing that the p25-Cdk5 complex in our cell system phosphorylates Rb directly without the need for any intermediary kinase activity. Hence, Rb might be an appropriate candidate that connects Cdk5 to cell-cycle deregulation during neuronal cell death

Phosphorylation of specific sets of tau isoforms reflects different neurofibrillary degeneration processes

AbstractTau proteins are the basic components of filaments that accumulate within neurons during neurofibrillary degeneration, a degenerating process with disease-specific phenotypes. This specificity is likely to be sustained by both phosphorylation state and isoform content of tau aggregates that form neuronal inclusions. In the present study, characterization of tau isoforms involved in neurofibrillary degeneration in Alzheimer's disease, Pick's disease, corticobasal degeneration and progressive supra-nuclear palsy was performed. Both analyses by immunoblotting using specific tau antibodies and cell transfection by tau isoform cDNAs allowed us to demonstrate the aggregation of (1) the six hyperphosphorylated tau isoforms in Alzheimer's disease, (2) tau isoforms without exon 10-encoding sequence in Pick's disease and (3) hyperphosphorylated exon 10-tau isoforms in corticobasal degeneration and progressive supranuclear palsy. Thus, neurofibrillary degeneration phenotypes are likely to be related to the phosphorylation of different combinations of tau isoforms (with and/or without exon 10-encoding sequence) in subpopulations of neurons

Loss of VGLUT1 and VGLUT2 in the prefrontal cortex is correlated with cognitive decline in Alzheimer disease.

International audienceSeveral lines of evidence suggest that the glutamatergic system is severely impaired in Alzheimer disease (AD). Here, we assessed the status of glutamatergic terminals in AD using the first available specific markers, the vesicular glutamate transporters VGLUT1 and VGLUT2. We quantified VGLUT1 and VGLUT2 in the prefrontal dorsolateral cortex (Brodmann area 9) of controls and AD patients using specific antiserums. A dramatic decrease in VGLUT1 and VGLUT2 was observed in AD using Western blot. Similar decreases were observed in an independent group of subjects using immunoautoradiography. The VGLUT1 reduction was highly correlated with the degree of cognitive impairment, assessed with the clinical dementia rating (CDR) score. A significant albeit weaker correlation was also observed with VGLUT2. These findings provide evidence indicating that glutamatergic systems are severely impaired in the A9 region of AD patients and that this impairment is strongly correlated with the progression of cognitive decline. Our results suggest that VGLUT1 expression in the prefrontal cortex could be used as a valuable neurochemical marker of dementia in AD

La maladie d’Alzheimer : une tauopathie parmi d’autres ?

La dégénérescence neurofibrillaire - agrégation intraneuronale de protéines tau anormalement phosphorylées - est un processus dégénératif qui affecte la région hippocampique des personnes âgées. Dans la maladie d’Alzheimer, la dégénérescence neurofibrillaire peut progresser vers les régions corticales associatives, selon un schéma établi, séquentiel et hiérarchique. À ce stade, les dépôts amyloïdes sont importants. Pour comprendre la maladie, il faut être capable de différencier la cause de la conséquence. Les formes familiales de la maladie d’Alzheimer ont mis en lumière le rôle majeur joué par le peptide β-amyloïde. Cependant, au cours des dernières années, une pièce maîtresse est venue modifier notre compréhension globale : un grand nombre de maladies neurodégénératives sont dues à des altérations directe ou indirecte du métabolisme de la protéine tau. Nous montrons ici que la maladie d’Alzheimer est une véritable « tauopathie », qui ne peut toutefois se développer qu’en présence d’un dysfonctionnement de l’APP, précurseur du peptide β-amyloïde

Purification, immunochemical and biological characterization of malate dehydrogenase of Schistosoma mansoni.

Journal Articleinfo:eu-repo/semantics/publishe

MicroRNA regulation of Alzheimer's Amyloid precursor protein expression

Gene dosage effects of Amyloid precursor protein (APP) can cause familial AD. Recent evidence suggest that microRNA (miRNA) pathways, implicated in gene transcriptional control, could be involved in the development of sporadic Alzheimer's disease (AD). We therefore investigated whether miRNAs could participate in the regulation of APP gene expression. We show that miRNAs belonging to the miR-20a family (that is, miR-20a, miR-17-5p and miR-106b) could regulate APP expression in vitro and at the endogenous level in neuronal cell lines. A tight correlation between these miRNAs and APP was found during brain development and in differentiating neurons. We thus identify miRNAs as novel endogenous regulators of APP expression, suggesting that variations in miRNA expression could contribute to changes in APP expression in the brain during development and disease. This possibility is further corroborated by the observation that a statistically significant decrease in miR-106b expression was found in sporadic AD patients.status: publishe

Tau story : des démences fronto-temporales aux autres tauopathies

Les protéines tau sont des protéines associées aux microtubules. Elles sont principalement exprimées dans les neurones. Il existe six isoformes de protéines tau dans le cerveau humain adulte générées par épissage alternatif à partir d’un gène unique situé sur le chromosome 17. Ces protéines jouent un rôle dans la polymérisation et la stabilité des microtubules. Cette fonction est régulée par l’état de phosphorylation des protéines tau. Dans de nombreuses maladies neurodégénératives regroupées sous le terme tauopathies, des formes anormalement phosphorvlées d’isoformes de protéines tau s’agrègent en filaments. La phosphorylation anormale et le rapport entre les différentes isoformes de protéines tau sont primordiaux dans l’étiopathogenèse de la dégénérescence neurofibrillaire. Ces facteurs peuvent être modulés de façon directe (ululations sur le gène de tau dans certaines formes familiales de démence fronto-temporale avec syndrome parkinsonien) ou indirecte (répétitions de triplets CTG dans la dystrophie myotonique de Steinert)