The majority of early-onset cases of familial Alzheimer's disease (FAD) are linked to mutations in two related genes, PS1 and PS2, located on chromosome 14 and 1, respectively. Using two highly specific antibodies against nonoverlapping epitopes of the PS1-encoded polypeptide, termed presenilin 1 (PS1), we document that the preponderant PS1-related species that accumulate in cultured mammalian cells, and in the brains of rodents, primates, and humans are approximately 27-28 kDa N-terminal and approximately 16-17 kDa C-terminal derivatives. Notably, a FAD-linked PS1 variant that lacks exon 9 is not subject to endoproteolytic cleavage. In brains of transgenic mice expressing human PS1, approximately 17 kDa and approximately 27 kDa PS1 derivatives accumulate to saturable levels, and at approximately 1:1 stoichiometry, independent of transgene-derived mRNA. We conclude that PS1 is subject to endoproteolytic processing in vivo.
Mutations in the presenilin 1 (PS1) and presenilin 2 genes cosegregate with the majority of early-onset familial Alzheimer's disease (FAD) pedigrees. We now document that the Abeta1-42(43)/Abeta1-40 ratio in the conditioned media of independent N2a cell lines expressing three FAD-linked PS1 variants is uniformly elevated relative to cells expressing similar levels of wild-type PS1. Similarly, the Abeta1-42(43)/Abeta1-40 ratio is elevated in the brains of young transgenic animals coexpressing a chimeric amyloid precursor protein (APP) and an FAD-linked PS1 variant compared with brains of transgenic mice expressing APP alone or transgenic mice coexpressing wild-type human PS1 and APP. These studies provide compelling support for the view that one mechanism by which these mutant PS1 cause AD is by increasing the extracellular concentration of Abeta peptides terminating at 42(43), species that foster Abeta deposition.
Accumulations of insoluble deposits of amyloid b-peptide are major pathological hallmarks of Alzheimer disease. Amyloid b-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the b-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. b-and g-secretase liberate by sequential cleavage the neurotoxic amyloid b-peptide, whereas a-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid b-peptide generation and therefore disease onset and progression.
Mutations in presenilin genes account for the majority of the cases of the familial form of Alzheimer's disease (FAD). Presenilin is essential for gamma-secretase activity, a proteolytic activity involved in intramembrane cleavage of Notch and beta-amyloid precursor protein (betaAPP). Cleavage of betaAPP by FAD mutant presenilin results in the overproduction of highly amyloidogenic amyloid beta42 peptides. gamma-Secretase activity requires the formation of a stable, high-molecular-mass protein complex that, in addition to the endoproteolysed fragmented form of presenilin, contains essential cofactors including nicastrin, APH-1 (refs 15-18) and PEN-2 (refs 16, 19). However, the role of each protein in complex formation and the generation of enzymatic activity is unclear. Here we show that Drosophila APH-1 (Aph-1) increases the stability of Drosophila presenilin (Psn) holoprotein in the complex. Depletion of PEN-2 by RNA interference prevents endoproteolysis of presenilin and promotes stabilization of the holoprotein in both Drosophila and mammalian cells, including primary neurons. Co-expression of Drosophila Pen-2 with Aph-1 and nicastrin increases the formation of Psn fragments as well as gamma-secretase activity. Thus, APH-1 stabilizes the presenilin holoprotein in the complex, whereas PEN-2 is required for endoproteolytic processing of presenilin and conferring gamma-secretase activity to the complex.
Intracellular trafficking and proteolytic processing of amyloid precursor protein (APP) have been the focus of numerous investigations over the past two decades. APP is the precursor to the amyloid -protein (A), the 38 -43-amino acid residue peptide that is at the heart of the amyloid cascade hypothesis of Alzheimer disease (AD). Tremendous progress has been made since the initial identification of A as the principal component of brain senile plaques of individuals with AD. Specifically, molecular characterization of the secretases involved in A production has facilitated cell biological investigations on APP processing and advanced efforts to model AD pathogenesis in animal models. This minireview summarizes salient features of APP trafficking and amyloidogenic processing and discusses the putative biological functions of APP. APP Gene FamilyThe human APP 3 gene, located on chromosome 21, was first identified in 1987 by several laboratories independently using partial protein sequence information obtained by the Glenner and Beyreuther/Masters laboratories several years earlier.More than 25 mutations in APP have been identified that are causative of the hereditary form of familial AD and a related condition of hereditary cerebral amyloid angiopathy. These mutations introduce amino acid substitutions within or flanking the A domain (for a listing of the mutations, see the Alzheimer Disease & Frontotemporal Dementia Mutation Database at www.molgen.ua.ac.be/ADMutations/). Moreover, APP gene duplication alone also causes early-onset AD with cerebral amyloid angiopathy. The latter findings fit nicely with the consistent finding of AD changes in individuals with trisomy 21 (Down syndrome), in which the APP gene is triplicated. Nonetheless, although mutations in APP are found only in rare cases of AD, they are nevertheless important because they provided early and seminal evidence that APP and A play a central role in AD pathogenesis.APP is now known to be one of three members of a small gene family, which includes APLP1 and APLP2 (human), Appl (fly), and apl-1 (worm). All encode type I membrane proteins with a large extracellular domain and a short cytoplasmic region that undergo similar processing (see below). Notably, only APP, but not any of the other APP-related genes, contains sequence encoding the A domain. APP ProcessingTwo predicted cleavages, one in the extracellular domain (-secretase cleavage) and the other in the transmembrane region (␥-secretase cleavage), are necessary to release A from the precursor molecule (Fig. 1). APP is first cleaved within the lumenal domain by -or ␣-secretase, resulting in the shedding of nearly the entire ectodomain and generation of membranetethered -or ␣-C-terminal fragments, respectively. The -and ␣-C-terminal fragments are subsequently cleaved within the transmembrane domain by ␥-secretase to release A (4 kDa) and p3 (3 kDa) peptides, respectively, into the extracellular milieu. In addition, ␥-secretase cleavage generates a cytoplasmic polypeptide termed AICD.AP...
In this work we demonstrate a facile means to generate fluorescent carbon nanoribbons, nanoparticles, and graphene from graphite electrode using ionic liquid-assisted electrochemical exfoliation. A time-dependence study of products exfoliated from the graphite anode allows the reconstruction of the exfoliation mechanism based on the interplay of anodic oxidation and anion intercalation. We have developed strategies to control the distribution of the exfoliated products. In addition, the fluorescence of these carbon nanomaterials can be tuned from the visible to ultraviolet region by controlling the water content in the ionic liquid electrolyte.
We report on the development of highly conductive NiCo2S4 single crystalline nanotube arrays grown on a flexible carbon fiber paper (CFP), which can serve not only as a good pseudocapacitive material but also as a three-dimensional (3D) conductive scaffold for loading additional electroactive materials. The resulting pseudocapacitive electrode is found to be superior to that based on the sibling NiCo2O4 nanorod arrays, which are currently used in supercapacitor research due to the much higher electrical conductivity of NiCo2S4. A series of electroactive metal oxide materials, including CoxNi1-x(OH)2, MnO2, and FeOOH, were deposited on the NiCo2S4 nanotube arrays by facile electrodeposition and their pseudocapacitive properties were explored. Remarkably, the as-formed CoxNi1-x(OH)2/NiCo2S4 nanotube array electrodes showed the highest discharge areal capacitance (2.86 F cm(-2) at 4 mA cm(-2)), good rate capability (still 2.41 F cm(-2) at 20 mA cm(-2)), and excellent cycling stability (∼ 4% loss after the repetitive 2000 cycles at a charge-discharge current density of 10 mA cm(-2)).
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