Biomedical subjects

Pascal Kurosinski

Publications and source records attributed to Pascal Kurosinski.

4 recordsLinked to original sources

PubMed2005

Active immunization trial in Abeta42-injected P301L tau transgenic mice.

Amyloid beta-peptide (Abeta) containing plaques and neurofibrillary tangles (NFT) are the two major histopathological hallmarks of Alzheimer's disease (AD). According to the amyloid cascade hypothesis, deposition of Abeta is an initial and essential step in the pathogenesis of AD, and formation of NFT has been proposed to be caused by increased Abeta levels. Several previous studies revealed that Abeta plaque formation can be reduced or even prevented by active immunization with Abeta preparations or by administration of Abeta-specific antibodies. To assess the role of fibrillar preparations of Abeta42 in NFT formation, we previously performed intracerebral (i.c.) injections of Abeta42 into brains of NFT-forming P301L tau transgenic mice which caused significant increases in NFT numbers. To determine whether these increases in NFT can be blocked or reduced by active immunization, P301L tau mice were immunized with intraperitoneal injections of preaggregated Abeta42. Abeta42-specific titers were monitored and the mice injected i.c. with Abeta42. We found that i.c. injection of Abeta42 caused significant increases in NFT formation. However, this induction was not affected by active immunization despite high serum anti-Abeta42 titer levels and binding of anti-Abeta42 antibodies to the injected Abeta42 aggregates. We conclude that active immunization is not sufficient to prevent the effect of Abeta42 on tau aggregation in our model system. Further studies are required to determine whether modifications of our protocol could affect the Abeta42-mediated induction of NFT formation.

Alzheimer Disease↗

PubMed2003

Activation of the ERK and JNK signaling pathways caused by neuron-specific inhibition of PP2A in transgenic mice.

A reduced activity of protein phosphatase 2A (PP2A) has been shown in brains of patients with Alzheimer's disease (AD), a neurodegenerative disorder characterized histopathologically by amyloid plaques and neurofibrillary tangles. Tau, as the principal component of neurofibrillary tangles, can be hyperphosphorylated by a reduced activity of PP2A in vitro and by pharmacological approaches, suggesting a crucial role of PP2A in tangle formation. To dissect the role of PP2A in vivo, we previously generated transgenic mice with chronically reduced PP2A activity by expressing a dominant-negative mutant form of the PP2A catalytic subunit Calpha, L199P, under the control of a neuron-specific promoter. In these mice, endogenous tau is phosphorylated at the epitopes Ser202/Thr205 and Ser422. In vitro, these tau phospho-epitopes can be phosphorylated by the kinases ERK and JNK, and the kinases themselves are negatively regulated by PP2A. In this study, we show that chronic inhibition of PP2A activity in L199P transgenic mice causes the activation of ERK and JNK as demonstrated by the phosphorylation and nuclear accumulation of the ERK and JNK substrates, Elk-1 and c-Jun. TUNEL staining revealed that activated JNK signaling was not associated with cell death. Our findings imply that PP2A is a negative regulator of the ERK and JNK signaling pathways in vivo, suggesting that in AD, tau hyperphosphorylation may be caused in part by PP2A dysfunction.

Animals↗

PubMed2002

Glial cells under physiologic and pathologic conditions.

Glial cells have long been considered to play roles in the nervous system that are unexciting compared with those of neurons. They provide neurons with nutrients, guide migrating neurons and their precursors during development, and dispose of the brain's "waste." Recent evidence, however, suggests that glial cells play more sophisticated, neuronlike roles. They integrate neuronal input, modulate synaptic activity, and process signals related to learning and memory. These findings have significant implications for humans with neurodegenerative diseases. In addition to activation on nervous system injury and during neuronal degeneration, glial cells also degenerate in several neurodegenerative diseases. Therefore, glial cell loss may contribute to the impairment of learning and memory. Therapeutic approaches to combat human neurodegenerative diseases thus need to restore the function of both neurons and glial cells.

Cell Transplantation↗

PubMed2002

Alzheimer's and Parkinson's disease--overlapping or synergistic pathologies?

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders in humans. They are characterized by insoluble protein deposits; beta-amyloid plaques and tau-containing neurofibrillary lesions in AD, and alpha-synuclein-containing Lewy bodies in PD. As a significant percentage of patients have clinical and pathological features of both diseases, the patho-cascades of the two diseases might overlap. For the first time, new animal models that express multiple transgenes provide the tools to dissect the pathogenic pathways and to differentiate between additive and synergistic effects.

Alzheimer Disease↗