BACE and γ-Secretase Characterization and Their Sorting as Therapeutic Targets to Reduce Amyloidogenesis

Marks, Neville; Berg, Martin J.

doi:10.1007/s11064-009-0054-1

Cited by 36 publications

(35 citation statements)

References 446 publications

(225 reference statements)

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“…As described previously, we detected APP CTFs exclusively in the endosomal fraction of wild-type SHSY5Y (Fig. 3b) (Marks and Berg 2010). Surprisingly, CTF appearance is completely abolished after treatment with the PI3K inhibitor LY294002 (Fig.…”

Section: Pi3-kinase Signaling Regulates Endosomal App Processingsupporting

confidence: 81%

“…These findings suggest that PI3K activated by IRS-2 promotes CTF formation. Previous work indicated that endosomal APP procession is mainly mediated via α-secretase activity (Marks and Berg 2010). Therefore, we analyzed the effect of α-, β-, and γ-secretase inhibitors on endogenous CTF formation and protein abundance of BACE-1, ADAM-10, and TACE in the different membrane fractions (Fig.…”

Section: Pi3-kinase Signaling Regulates Endosomal App Processingmentioning

confidence: 99%

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Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer’s disease

Stöhr

Schilbach

Moll

et al. 2011

AGE

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Section: Pi3-kinase Signaling Regulates Endosomal App Processingsupporting

confidence: 81%

Section: Pi3-kinase Signaling Regulates Endosomal App Processingmentioning

confidence: 99%

Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer’s disease

Stöhr

Schilbach

Moll

et al. 2011

AGE

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“…166,167) Furthermore, another LXR agonist GW3965 reduced Ab levels and amyloid plaques, enhanced apo E expression, and improved memory deficits in a mouse model of AD (Tg2576). 168) Recently, a relationship has been suggested between SorLA and AD 124,169,170) because SorLA gene variants are associated with sporadic AD. 171) When the AD model mice (APPSwe/PS1DE9) were crossed with SorLA-deficient mice, AD pathology occurred earlier that in the AD model mice expressing SorLA.…”

Section: Lipid Metabolism and Admentioning

confidence: 99%

Lipid Metabolism and Glial Lipoproteins in the Central Nervous System

Hayashi

2011

Biological & Pharmaceutical Bulletin

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INTRODUCTIONFunctions of the central nervous system (CNS) are performed mainly by neurons and glia-primarily astrocytes, microglia and oligodendrocytes. It has been thought for a long time that glia only passively support neurons, but we now know that glia actively attend to assist in neuronal functions like synaptogenesis and neurotransmission. 1) Although it was believed that ca. 90% of the cells in the brain are glia and the rest of cells are neurons, Azevedo et al. recently reported that the numbers of neurons and non-neuronal cells (glia) are close to equal in human adult brain.2) Brain is the most cholesterol-rich organ in the body, and cholesterol metabolism in the CNS is tightly regulated between neurons and glia. [3][4][5][6][7] Imbalances in the metabolism of lipids, especially cholesterol, are closely linked to the development of several neurodegenerative disorders such as Alzheimer's disease, 8,9) Niemann-Pick type C disease 10) and Smith-Lemli Opitz syndrome. 11,12) In this review the regulation of lipid metabolism and the roles of glial lipoproteins in the CNS will be discussed. LIPID HOMEOSTASIS IN THE CNSThe system of lipid metabolism and transport in the CNS is different from that in peripheral tissues because the CNS is segregated from the peripheral circulation by the blood-brain barrier (BBB).13) Although lipoprotein particles can cross the BBB in vivo in Drosophila, which has a functional BBB like that in vertebrates, 14) lipoproteins in the mouse, rat and human do not cross the BBB. Consequently, since labeled cholesterol peripherally administrated was not found in the CNS of mammals, 15,16) cholesterol in the CNS is derived from de novo synthesis inside of the CNS. Furthermore, in the plasma of subjects who had liver transplantation the genotype of apolipoprotein (apo) E was that of the donor, whereas the subjects retained the own apo E genotype in the cerebrospinal fluid (CSF).17) Moreover, lipoproteins in the CNS consist of only high density lipoprotein (HDL)-like particles in contrast to the circulation which contains very low density lipoproteins (VLDL), low density lipoproteins (LDL) and HDL. It is known that the HDL-like particles in the CNS are secreted from glia (glial lipoproteins), mainly astrocytes and microglia, under normal conditions, [18][19][20] however lipoproteins can be secreted from neurons in vitro 21,22) and in vivo 23) under some specific conditions. Unesterified cholesterol is the major sterol in the adult brain, and small amounts of desmosterol and cholesteryl ester are also present. The majority (70-80%) of cholesterol in the adult brain is in myelin formed by oligodendrocytes. 24)Thus, the activity of cholesterol synthesis in the CNS is the highest during the myelinogenesis. After myelination, cholesterol synthesis continues at very low level in the CNS, and occurs mainly in astrocytes. 5,13,24) Neurons do not efficiently synthesize cholesterol and rely on external source of cholesterol from astrocytes, 25) so that neurons take up cholesterol as lipoproteins via ...

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“…Refi nements include substitution of additional hydrophobic residues to improve passage through the bloodbrain barrier. The search for BACE-1 inhibitors continues, and this enzyme remains a potential target for therapeutic approaches (Vassar et al 2009;Marks and Berg 2010 ;Hunt and Turner 2009;Hills and Vacca 2007 ) .…”

Section: B -Secretase Inhibitorsmentioning

confidence: 99%

Strategies for Inhibiting Protein Aggregation: Therapeutic Approaches to Protein-Aggregation Diseases

Lanning

Meredith

2011

Non-Fibrillar Amyloidogenic Protein Assemblies - Common Cytotoxins Underlying Degenerative Diseases

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Self-aggregation of proteins and peptides is at the root of many diseases, especially neurodegenerative diseases. These conditions include Alzheimer's disease, Huntington's disease, Parkinson's disease, type-2 diabetes mellitus, and transmissible spongiform encephalopathies, which are associated with self-aggregation of amyloid b -protein (A b ), huntingtin, a -synuclein, islet amyloid polypeptide, and the prion protein, respectively. The list of diseases for which protein/peptide aggregation is the root cause is ever expanding. There does not appear to be a single biochemical mechanism by which proteins and peptides self-associate, or a single pathogenic mechanism to explain all protein-/peptide-aggregation diseases. Nevertheless, inhibition of protein self-aggregation remains a potential target for therapeutic intervention. Beyond therapy, inhibitors of protein self-aggregation can serve as tools to help us understand the mechanisms by which aggregation occurs and harms cells. In this chapter, we examine select examples of inhibitors of protein aggregation. We have divided aggregating proteins/peptides into two types: (1) Proteins that have an unstable tertiary structure, that unfold under cellular stress, or that fail to fold correctly during biosynthesis. This instability leads to persistence of unfolded domains that can act as a nidus for self-association. (2) Peptides or proteins (or protein domains) that cannot fold at all, or fold only in the presence of a bound ligand. Examples of the fi rst group include transthyretin, the mammalian prion protein, and certain point-mutant forms of lysozyme or a 1-antitrypsin. In general, self-aggregation of these proteins results from exposure of normally buried hydrophobic residues to aqueous media. Examples of the second group include A b , islet amyloid polypeptide, and calcitonin. Within the second group, we also include proteins that are "peptide-like" in having domains with no unique, stable

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BACE and γ-Secretase Characterization and Their Sorting as Therapeutic Targets to Reduce Amyloidogenesis

Cited by 36 publications

References 446 publications

Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer’s disease

Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer’s disease

Lipid Metabolism and Glial Lipoproteins in the Central Nervous System

Strategies for Inhibiting Protein Aggregation: Therapeutic Approaches to Protein-Aggregation Diseases

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