Francesca Argellati

GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non-emetic doses.

BACKGROUND AND PURPOSE Strategies designed to enhance cerebral cAMP have been proposed as symptomatic treatments to counteract cognitive deficits. However, pharmacological therapies aimed at reducing PDE4, the main class of cAMP catabolizing enzymes in the brain, produce severe emetic side effects. We have recently synthesized a 3‐cyclopentyloxy‐4‐methoxybenzaldehyde derivative, structurally related to rolipram, and endowed with selective PDE4D inhibitory activity. The aim of the present study was to investigate the effect of the new drug, namely GEBR‐7b, on memory performance, nausea, hippocampal cAMP and amyloid‐β (Aβ) levels.

Periostin: A Novel Prognostic and Therapeutic Target For Genitourinary Cancer?

Many of the cellular abnormalities present in solid tumors are structural in nature and involve the proteins of the extracellular matrix (ECM). Periostin is a protein produced and secreted by the fibroblasts as a component of the ECM where it is involved in regulating intercellular adhesion. The expression of periostin has an important physiological role during embryogenesis and growth, namely at the level of bone, dental, and cardiac tissues. Many studies indicate that periostin plays an important role for tumor progression in various types of cancer, such as colon, lung, head and neck, breast, ovarian, and prostate. To the best of our knowledge, a limited number of studies have investigated periostin expression in urogenital cancer, such as prostate, bladder, penile, and renal cancer, and no studies were performed in testis cancer. In this review article, we summarize the most recent knowledge of periostin, its genetic and protein structure, and the role of the different isoforms identified and sequenced so far. In particular, we focus our attention on the role of this protein in genitourinary tumors, trying to emphasize the role not only as a possible prognostic marker, but also as a possible target for the development of future anticancer therapies.

Evidence against the overexpression of APP in down syndrome

Down syndrome (DS) is the most common genetic disorder with mental retardation and is caused by trisomy 21. By the age of 40 years, virtually all adults with DS have sufficient neuropathology for a diagnosis of Alzheimers disease (AD), which is characterized by accumulation of amyloid‐beta in senile plaques and formation of neurofibrillary tangles. Amyloid‐beta derives from a longer precursor protein, APP, whose gene maps to chromosome 21. In DS, the early appearance of senile plaques is commonly associated with the presence of a third copy of the APP gene. Here we show DS brains and trisomic fibroblasts in which APP is not overexpressed, compared to euploid controls, challenging the notion that the widespread amyloid‐beta deposits, consistently found in DS individuals, result from an extra copy of APP. iubmb Life, 58: 103‐106, 2006

Protein kinase C-dependent α-secretory processing of the amyloid precursor protein is mediated by phosphorylation of myosin II-B

A substantial body of evidence indicates that protein kinase C (PKC) is involved in the α‐secretory processing of the amyloid precursor protein (APP), an event that reduces the formation of the pathogenic amyloid‐β peptide. Recently, we have shown that trafficking and processing of APP are both impaired by knockdown of myosin II‐B, one of the major neuronal motor proteins. Here, we provide evidence that the α‐secretory processing of APP is mediated by PKC‐dependent phosphorylation of myosin II‐B. This signaling pathway provides an important link between APP and the neuronal cytoskeleton and might be crucial for the understanding of the biological and pathological roles of APP.—Argellati, F., Domenicotti, C., Passalacqua, M., Janda, E., Melloni, E., Marinari, U. M., Pronzato, M. A., Ricciarelli, R. Protein kinase C‐dependent α‐secretory processing of the amyloid precursor protein is mediated by phosphorylation of myosin II‐B. FASEB J. 23, 1246–1251 (2009)

In vitro effect of PPAR-γ2 Pro12Ala polymorphism on the deposition of Alzheimer's amyloid-β peptides

Abstract Mounting evidence suggests that peroxisome proliferator-activated receptor-γ (PPAR-γ) is involved in the modulation of pathogenic events related to Alzheimers disease (AD). Such events would include the cerebral deposition of amyloid-β (Aβ) and the consequent local inflammatory response. PPAR-γ has been shown to act on both fronts, reducing either the secretion of Aβ or the expression of pro-inflammatory cytokines. Recently, the relatively common Pro12Ala polymorphism in exon 2 of PPAR-γ has been associated with higher risk for late onset AD. Here, we compare the effect of PPAR-γ and its genetic variant on the secretion of Aβ. Our results indicate that, in neuronal cultured cells, the Pro12Ala substitution does not affect the anti-amyloidogenic capacity of PPAR-γ. Additional factors, PPAR-γ related, may therefore predispose aged subjects, carrying the Ala allele, to develop the neurodegenerative disease.

Processing of the amyloid precursor protein: Role of protein kinase C and myosin IIB

beta peptide (Abeta) into insoluble aggregates known as plaques. Abeta is derived from the amyloid precursor protein (APP), with Abeta40 and Abeta42 the dominant peptide species. The precise mechanism of Abeta-induced neuronal toxicity remains unresolved. Since Abeta contains part of the putative transmembrane domain of the APP, the mechanism of Abtea mediated neurotoxicity may involve interactions with the cell membrane. We and others have previously reported that Abeta neurotoxicity is correlated with an increased affinity for the neuronal plasma membrane. Potential molecular targets on the cell membrane for Abeta includes lipids, proteoglycans, and proteins. Objective: To test if Abeta toxicity and cell membrane binding was receptor mediated i.e. required a stereospecific interaction. We synthesized Dand L-handed versions of Abeta42 because in the absence of a chiral environment, both the variants would behave identically and as such if a receptor was not required for toxicity then it would be expected that both peptides would be equally toxic. Methods: Various biophysical, membrane binding and neurotoxic properties were examined. Results: The results showed D-Abeta42 and L-Abeta42 are chemically equivalent with respect to copper binding, generation of reactive oxygen species and aggregation profiles. Cell binding studies show both peptides bound to cultured cortical neurons. However, only L-Abeta42 was neurotoxic and inhibited long term potentiation indicating L-Abeta42 requires a stereospecific target to mediate toxicity. We identified the lipid phosphatidylserine, as a potential target. Annexin V, which has very high affinity for externalized phosphatidylserine, significantly inhibited Lbut not DAbeta42 binding to the cultured cortical neurons and significantly rescued L-Abeta42 neurotoxicity. Conclusions: This suggests that Abeta mediated toxicity in Alzheimer disease is dependent upon Abeta binding to phosphatidylserine on neuronal cells.