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Background: Alzheimer's disease (AD) is one of the most common forms of dementia, is characterized by memory loss and cognitive impairment that affects more than 30 million people worldwide. The pathogenesis of Alzheimer's disease is primary driven by brain accumulation of the amyloid ß peptide generated from the amyloid-ß precursor protein (APP) via cleavages by ß- and -secretase. In this study, we propose an approach by molecular docking to select compounds as -secretase inhibitors for decreasing the APP generation. Methods: We selected potential -secretase inhibitors by molecular docking in the potential site between Asp257, Lue268, Asp385, Ile387, Phe388, and Leu432 amino acids in presenilin-1 (PS-1), using a chemical library of over 500,000 compounds. Results: Eight compounds (AZ1 - AZ8) were selected by molecular docking to develop -secretase inhibitors for decreasing the APP generation. Conclusion: AZ1 - AZ8 compounds could be interacting in the potential site between Asp257, Lue268, Asp385, Ile387, Phe388, and Leu432 amino acids in PS-1. These compounds could specifically interact in the binding pocket in PS-1 to prevent/decrease the APP generation, to develop a new drug against Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. The major pathological changes in AD progression are the generation and accumulation of amyloid-beta (Aβ) peptides as well as the presence of abnormally hyperphosphorylated tau proteins in the brain. Autophagy is a conserved degradation pathway that eliminates abnormal protein aggregates and damaged organelles. Previous studies have suggested that autophagy plays a key role in the production and clearance of Aβ peptides to maintain a steady-state of Aβ peptides levels. However, a growing body of evidence suggests that autophagy is significantly impaired in the pathogenesis of AD, especially in Aβ metabolism. Therefore, this article reviews the latest studies concerning the mechanisms of autophagy, the metabolism of Aβ peptides, and the defective autophagy in the production and clearance of Aβ peptides. Here, we also summarize the established and new strategies for targeting autophagy in vivo and through clinical AD trials to identify gaps in our knowledge and to generate further questions. [ABSTRACT FROM AUTHOR]

Objective: NGFR/p75NTR and NRADD/NRH proteins are closely related structurally and are encoded by genes that arose from a duplication event early in vertebrate evolution. The transmembrane domain (TMD) of NGFR is cleaved by γ-secretase but there is conflicting data around the susceptibility to γ-secretase cleavage of NRADD proteins. If NGFR and NRADD show differential susceptibility to γ-secretase, then they can be used to dissect the structural constraints determining substrate susceptibility. We sought to test this differential susceptibility. Results: We developed labelled, lumenally-truncated forms of zebrafish Ngfrb and Nradd and a chimeric protein in which the TMD of Nradd was replaced with the TMD of Ngfrb. We expressed these in zebrafish embryos to test their susceptibility to γ-secretase cleavage by monitoring their stability using western immunoblotting. Inhibition of γ-secretase activity using DAPT increased the stability of only the Ngfrb construct. Our results support that only NGFR is cleaved by γ-secretase. Either NGFR evolved γ-secretase-susceptibility since its creation by gene duplication, or NRADD evolved to be refractory to γ-secretase. Protein structure outside of the TMD of NGFR is likely required for susceptibility to γ-secretase. [ABSTRACT FROM AUTHOR]

The majority of mutations causing familial Alzheimer's disease (fAD) have been found in the gene PRESENILIN1 (PSEN1) with additional mutations in the related gene PRESENILIN2 (PSEN2). The best characterized function of PRESENILIN (PSEN) proteins is in γ-secretase enzyme activity. One substrate of γ-secretase is encoded by the gene AMYLOID BETA A4 PRECURSOR PROTEIN (AβPP/APP) that is a fAD mutation locus. AβPP is the source of the amyloid-β (Aβ) peptide enriched in the brains of people with fAD or the more common, late onset, sporadic form of AD, sAD. These observations have resulted in a focus on γ-secretase activity and Aβ as we attempt to understand the molecular basis of AD pathology. In this paper we briefly review some of the history of research on γ-secretase in AD. We then discuss the main ideas regarding the role of γ-secretase and the PSEN genes in this disease. We examine the significance of the "fAD mutation reading frame preservation rule" that applies to PSEN1 and PSEN2 (and AβPP) and look at alternative roles for AβPP and Aβ in fAD. We present a case for an alternative interpretation of published data on the role of γ-secretase activity and fAD-associated mutations in AD pathology. Evidence supports a "PSEN holoprotein multimer hypothesis" where PSEN fAD mutations generate mutant PSEN holoproteins that multimerize with wild type holoprotein and dominantly interfere with an AD-critical function(s) such as autophagy or secretion of Aβ. Holoprotein multimerization may be required for the endoproteolysis that activates PSENs' γ-secretase activity. [ABSTRACT FROM AUTHOR]

Notch history begins in 1919 with Thomas Hunt Morgan studies on fruit fly mutants. From then, this gene aroused lively interest in the scientific community since it is involved in a wide variety of processes, including morphogenesis, tissue homeostasis, and stem cell maintenance. Deregulation of Notch signaling characterizes several human tumors. Hematopoietic system is affected by mutations of Notch receptors, Notch ligands, and proteins controlling their stability. Approximately 60% T acute lymphoblastic leukemia (T-ALL) patients carry activating Notch1 mutations prompting blasts growth. In addition, multiple myeloma is characterized by Notch signaling hyper-activation due to an abnormal expression of the Jagged2 ligand; this affects not only myeloma cells, but also their interaction with bone marrow microenvironment, influencing tumor burden and bone disease. These findings make Notch a rational target of a therapeutic approach. Inhibitors of the Notch activating enzyme, γ-Secretase, have been successfully used in vitro and in vivo and are currently under clinical trials for T-ALL and breast cancer. Yet a wide use of these inhibitors is prevented by frequently occurring drug resistance. To elucidate the mechanism underlying this phenomenon, a number of pathways have been identified mediating Notch biological effects: AKT and c-Myc are frequently deregulated in leukemic patients and account for resistance to γ-Secretase inhibitors by acting downstream Notch receptor. Therefore, the interaction of Notch with other cancer-associated proteins should be clarified to predict the biological outcome of a Notch targeted therapy and possibly, to exploit combined treatments against the key deregulated elements in Notch-associated cancers. [ABSTRACT FROM AUTHOR]

Abstract: Intraneuronal punctate immunostaining in Alzheimer’s disease brain and amyloid-β precursor protein (APP) transgenic mice has been suggested to represent Aβ, but this is somewhat controversial. Here we show that both biochemical Aβ levels and intraneuronal immunostaining are reduced in APP transgenic mice when γ-secretase is inhibited. Moreover, BACE-1 deficient APP transgenic mice show neither Aβ production nor intraneuronal immunostaining. Our findings suggest that the punctate immunostaining with APP antibodies is due to Aβ that has accumulated inside neurons. Similar type of intraneuronal Aβ accumulation, which precedes senile plaque formation, may link Aβ to tauopathy and neurodegeneration in Alzheimer’s disease pathogenesis. [Copyright &y& Elsevier]