Voyage au bout de la nuit: Aß and tau imaging in dementias.

The last decade has witnessed the development and characterization of tracers for the evaluation of neuropathology in vivo. The introduction of these tracers, namely ß-amyloid (Aß) and later tau, are providing the tools to change the landscape and refine our understanding of Aß and tau deposition in the brain, allowing to investigate the causes, refine diagnosis and improve treatment of major neurodegenerative conditions such as Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE) and frontotemporal lobar degeneration (FTLD). Aß and tau imaging allow examination of the regional and global changes of these disease markers over time as well as their relationship with other relevant parameters such as cognitive performance and neurodegenerative changes. Aß and tau imaging will enable to establish the role Aß and tau play -and interplay- in aging and disease. Aß and tau imaging value resides in being not only diagnostic, prognostic or progression markers, but also surrogate markers of disease, crucial for patient recruitment and efficacy evaluation of disease-specific therapies.

La lunga attesa: towards a molecular approach to neuroimaging and therapeutics in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by the gradual onset of dementia. The pathological hallmarks of the disease are Aß amyloid plaques, neurofibrillary tangles (NFT), synaptic loss and reactive gliosis. Current diagnosis of AD is made by clinical, neuropsychologic, and neuroimaging assessments. Routine structural neuroimaging evaluation with computed tomography (CT) and magnetic resonance imaging (MRI) is based on non-specific features such as atrophy, a late feature in the progression of the disease, hence the crucial importance of developing new approaches for early and specific recognition at the prodromal stages of AD. Functional neuroimaging techniques such as functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), positron emission tomography (PET) and single photon emission computed tomography (SPECT), possibly in conjuction with other related Aß biomarkers in plasma and CSF, could prove to be valuable in the differential diagnosis of AD, as well as in assessing prognosis. With the advent of new therapeutic strategies aimed at reducing the Aß amyloid burden in the brain, there is increasing interest in the development of MRI contrast agents and PET and SPECT radioligands that will permit the assessment of Aß amyloid burden in vivo. - ma dov'è / la lenta processione di stagioni / che fu un'alba infinita e senza strade, / dov'è la lunga attesa e qual è il nome / del vuoto che ci invade. - Eugenio Montale.

Cellular stress regulates the nucleocytoplasmic distribution of the protein-tyrosine phosphatase TCPTP.

Specific cellular stresses, including hyperosmotic stress, caused a dramatic but reversible cytoplasmic accumulation of the otherwise nuclear 45-kDa variant of the protein-tyrosine phosphatase TCPTP (TC45). In the cytoplasm, TC45 dephosphorylated the epidermal growth factor receptor and down-regulated the hyperosmotic stress-induced activation of the c-Jun N-terminal kinase. The hyperosmotic stress-induced nuclear exit of TC45 was not inhibited by leptomycin B, indicating that TC45 nuclear exit was independent of the exportin CRM-1. Moreover, hyperosmotic stress did not induce the cytoplasmic accumulation of a green fluorescent protein-TC45 fusion protein that was too large to diffuse across the nuclear pore. Our results indicate that TC45 nuclear exit may occur by passive diffusion and that cellular stress may induce the cytoplasmic accumulation of TC45 by inhibiting nuclear import. Neither p42(Erk2) nor the stress-activated c-Jun N-terminal kinase or p38 mediated the stress-induced redistribution of TC45. We found that only those stresses that stimulated the metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) induced the redistribution of TC45. In addition, specific pharmacological activation of the AMPK was sufficient to cause the accumulation of TC45 in the cytoplasm. Our studies indicate that specific stress-activated signaling pathways that involve the AMPK can alter the nucleocytoplasmic distribution of TC45 and thus regulate TC45 function in vivo.

The protein tyrosine phosphatase TCPTP suppresses the tumorigenicity of glioblastoma cells expressing a mutant epidermal growth factor receptor.

Glioblastoma multiforme (GBM) is the most aggressive type of glioma and GBMs frequently contain amplifications or mutations of the EGFR gene. The most common mutation results in a truncated receptor tyrosine kinase known as Delta EGFR that signals constitutively and promotes GBM growth. Here, we report that the 45-kDa variant of the protein tyrosine phosphatase TCPTP (TC45) can recognize Delta EGFR as a cellular substrate. TC45 dephosphorylated Delta EGFR in U87MG glioblastoma cells and inhibited mitogen-activated protein kinase ERK2 and phosphatidylinositol 3-kinase signaling. In contrast, the substrate-trapping TC45-D182A mutant, which is capable of forming stable complexes with TC45 substrates, suppressed the activation of ERK2 but not phosphatidylinositol 3-kinase. TC45 inhibited the proliferation and anchorage-independent growth of Delta EGFR cells but TC45-D182A only inhibited cellular proliferation. Notably, neither TC45 nor TC45-D182A inhibited the proliferation of U87MG cells that did not express Delta EGFR. Delta EGFR activity was necessary for the activation of ERK2, and pharmacological inhibition of ERK2 inhibited the proliferation of Delta EGFR-expressing U87MG cells. Expression of either TC45 or TC45-D182A also suppressed the growth of Delta EGFR-expressing U87MG cells in vivo and prolonged the survival of mice implanted intracerebrally with these tumor cells. These results indicate that TC45 can inhibit the Delta EGFR-mediated activation of ERK2 and suppress the tumorigenicity of Delta EGFR-expressing glioblastoma cells in vivo.