Amyloid Precursor Protein Trafficking, Processing, and Function

Department of Neurobiology, The University of Chicago, Chicago, Illinois 60637, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 10/2008; 283(44):29615-9. DOI: 10.1074/jbc.R800019200
Source: PubMed


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 β-protein (Aβ), 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 Aβ as the principal component of brain senile plaques of individuals with AD. Specifically, molecular characterization
of the secretases involved in Aβ 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.

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    • "Yet, the process of amyloid formation and the role they play in the physiopathology of disease remains unclear. Of interest, there is accumulating evidence for the involvement of endosomal compartments in amyloid homeostasis (Thinakaran and Koo, 2008). In particular, amyloidogenic proteins and peptides accumulate in multivesicular endosomes (MVEs) and aggregate as toxic oligomers (Takahashi et al., 2002). "
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    ABSTRACT: Accumulation of toxic amyloid oligomers is a key feature in the pathogenesis of amyloid-related diseases. Formation of mature amyloid fibrils is one defense mechanism to neutralize toxic prefibrillar oligomers. This mechanism is notably influenced by apolipoprotein E variants. Cells that produce mature amyloid fibrils to serve physiological functions must exploit specific mechanisms to avoid potential accumulation of toxic species. Pigment cells have tuned their endosomes to maximize the formation of functional amyloid from the protein PMEL. Here, we show that ApoE is associated with intraluminal vesicles (ILV) within endosomes and remain associated with ILVs when they are secreted as exosomes. ApoE functions in the ESCRT-independent sorting mechanism of PMEL onto ILVs and regulates the endosomal formation of PMEL amyloid fibrils in vitro and in vivo. This process secures the physiological formation of amyloid fibrils by exploiting ILVs as amyloid nucleating platforms.
    Cell Reports 09/2015; 13(1). DOI:10.1016/j.celrep.2015.08.057 · 8.36 Impact Factor
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    • "Although the cause of neuronal degeneration is unknown, several researchers have pointed out that Ab accumulation positively correlates with neuronal death (Shirwany et al., 2007; Thinakaran and Koo, 2008). The neurotoxic effect of the Ab peptide is mediated, at least in part, by the increased production of reactive oxygen and nitrogen species, which cause oxidative damage to macromolecules such as DNA, proteins, and lipids (Butterfield, 2002; Chauhan and Chauhan, 2006). "
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    ABSTRACT: The Aβ peptide-mediated toxicity participates in the neuronal death that occurs in Alzheimer's disease. The present study aims to isolate the major compounds of Serjania erecta Radlk leaves and assess whether these compounds protect PC12 cells from Aβ25-35 peptide-induced toxicity. We isolated three flavonoid glycosides with high purity: quercetrin, vitexin, and isovitexin. The Aβ25-35 peptide alone decreased the PC12 cell viability in a concentration-dependent manner, as evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay. We selected the Aβ25-35 peptide concentration of 50 μM for the experiments. Treatment of PC12 cells with the flavonoids before exposure to the Aβ25-35 peptide increased cell viability, i.e., these compounds protected the cells against Aβ25-35 peptide-induced toxicity. Vitexin promoted higher protection levels than quercetrin and isovitexin, and reduced the lactate dehydrogenase release and NO production in Aβ25-35 peptide-treated PC12 cells. Therefore, the glycosylated flavonoids that exist in S. erecta leaves, especially vitexin, protect PC12 cells from Aβ25-35 peptide-induced toxicity.
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    • "There are 8 isoforms of APP (695-770AA); the 695 amino acid isoform is highly expressed in the CNS (major neuronal form). Studies on APP overexpression demonstrated that it positively modulates cell survival and growth [46]. APP promotes neurite arborization in a Drosophila model of brain injury [47]. "
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    ABSTRACT: A common feature of neurodegenerative diseases is the formation of misfolded, mostly enzyme resistant proteins. These substances may form toxic assemblies according to the current concept of the neurodegenerative diseases. Overlapping of the misfolded proteins is typical in these disorders. The formation of misfolded proteins and toxic aggregates point to a common pathway of these disorders: failure in normal protein folding in the ER as a consequence of ER-stress and mitochondrial energy production. Alzheimer's disease (AD) is a rather heterogeneous, multifactorial disorder with wide clinical heterogeneity and is classified into several subtypes. In AD the processing of the amyloid precursor protein (APP) and formation of toxic β-amyloid (Aβ) structures occur intraneuronally. Aβ affects both ER and mitochondria and disturbs Ca2+-homeostasis of the cells. Mitochondrial dysfunction is one of the main pathological events in AD. Mitochondria accumulate Aβ derived from the ER/Golgi or from the mitochondriaassociated ER-membranes (MAM). Free radicals, oxidative stress and increasing Ca2+-concentration in mitochondria cause decreased ATP production. Mitochondrial dynamic and trafficking are also altered as a result of Aβ toxicity. Synaptic mitochondria show a very high vulnerability. Depletion of Ca2+ level in the ER results in dysfunction of protein folding and evokes unfolded protein response (UPR), and affects also mitochondria. MAM may play special role in the ERmitochondria cross talk. Mitochondria themselves (using mitochondria-targeting antioxidants such as MitoQ) could be a special target for AD treatment. Another targets are the UPR cascade proteins (PERK, IRE1, ATF6) and receptors involved in Ca2+ -level stabilization of the ER (Ryr, IP3R).
    Current Alzheimer research 07/2015; 12(7). DOI:10.2174/1567205012666150710095035 · 3.89 Impact Factor
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