Generation of Amyloidogenic C-terminal Fragments during Rapid Axonal Transport in Vivo of β-Amyloid Precursor Protein in the Optic Nerve

Amaratunga, Anil; Fine, Richard E.

doi:10.1074/jbc.270.29.17268

Cited by 45 publications

(33 citation statements)

References 38 publications

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“…Both ␣-and ␤-cleavage of APP has been reported in the optic nerve of rabbit (15,31), although those data suggested that the proteolysis of neuronal APP occurred at the axolemma. Were proteolysis to occur in the transport vesicle in the axon, the C-terminal lacking fragment of APP could continue to undergo fast axonal transport to the presynaptic terminus and thus contribute to signal in ROI f in excess of the local proteolysis, which peaks at 8 h post-radiolabeling.…”

Section: Effects Of Synaptic Activity On App/aplp2mentioning

confidence: 78%

Post-translational Processing and Turnover Kinetics of Presynaptically Targeted Amyloid Precursor Superfamily Proteins in the Central Nervous System

Lyckman

Confaloni

Wang

et al. 1998

Journal of Biological Chemistry

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The amyloid precursor superfamily is composed of three highly conserved transmembrane glycoproteins, the amyloid precursor protein (APP) and amyloid precursor-like proteins 1 and 2 (APLP1, APLP2), whose functions are unknown. Proteolytic cleavage of APP yields the ␤A4 peptide, the major component of cerebral amyloid in Alzheimer's disease. Here we show that five post-translationally modified, full-length species of APP and APLP2 (but not APLP1) arrive at the mature presynaptic terminal in the fastest wave of axonal transport and are subsequently rapidly cleared (mean halflife of 3.5 h). Rapid turnover of presynaptic APP and APLP2 occurs independently of visual activity. Turnover of the most rapidly arriving APP species was accompanied by a delayed accumulation of a 120-kDa, APP fragment lacking the C terminus, consistent with presynaptic APP turnover via constitutive proteolysis. Turnover of APLP2 was not accompanied by detectable APLP2 fragment peptides, suggesting either that APLP2 either is more rapidly degraded than is APP or is retrogradely transported shortly after reaching the terminus. A single 150-kDa APLP2 species containing the Kunitz protease inhibitor domain is the major amyloid precursor superfamily protein transported to the presynapse. Presynaptic APP and APLP2 are sialylated and N-and O-glycosylated, and some also carry chondroitin sulfate glycosaminoglycan and/or dermatan sulfate glycosaminoglycan. The rapid kinetics for turnover of APP and APLP2 predict a sensitive balance of synthesis, transport, and elimination rates that may be critical to normal neuronal functions and metabolic fates of these proteins.Alzheimer's disease is an age-related human dementia whose principle neuropathological signs are forebrain cholinergic neuronal death, neurofibrilliary tangles, and amyloidosis of cerebral vessels and senile plaques (1). Interest in the regulation of APP 1 expression arose from it being recognized as the parent protein of ␤A4, the major peptide constituent of cerebrovascular and senile plaque amyloid (2). APP is one of the three proteins encoded by genes in the mammalian amyloid precursor superfamily (APSF; see Fig. 1A), which also has two genes encoding APLP1 and APLP2 (3). Although the APP gene is the only APSF gene that encodes ␤A4, the conservation of gene structure (4) and domain homology (5) among the APSF proteins suggests that they may share significant overlap in function and expression, and thus, that amyloidogenic processing of APP may be influenced in parallel with processing of APLP1 and/or APLP2. For instance, APSF proteins from various phyla share highly conserved extracellular zinc and heparin binding domains (3), single membrane-spanning domains (4, 6), and intracellular phosphorylation sites (7). Additionally, APP and APLP2 genes both contain N-linked glycosylation sites (8), splice-specific chondroitin sulfate glycosaminoglycan (CSGAG) attachment sites (9 -11), and, alternatively, spliced exons that encode the Kunitz protease inhibitor (KPI) domain (4, 12). Various combinat...

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Section: Effects Of Synaptic Activity On App/aplp2mentioning

confidence: 78%

Post-translational Processing and Turnover Kinetics of Presynaptically Targeted Amyloid Precursor Superfamily Proteins in the Central Nervous System

Lyckman

Confaloni

Wang

et al. 1998

Journal of Biological Chemistry

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“…However, it is not a general effect because nicastrin, VLDLR, and LARR maturation are not affected. BACE (Capell et al, 2000) and APP (Caporaso et al, 1992) are subject to glycosylation, before APP is then cleaved in the secretory pathway in cultured cells (Tomita et al, 1998) or after it has entered into the fast axonal transport pathway in neurons (Koo et al, 1990;Amaratunga and Fine, 1995;Buxbaum et al, 1998;Kamal et al, 2001). By altering BACE and APP trafficking and maturation, GGA1 might therefore be expected to have implications for APP processing.…”

Section: Discussionmentioning

confidence: 99%

GGA1 Acts as a Spatial Switch Altering Amyloid Precursor Protein Trafficking and Processing

Arnim¹,

Spoelgen²,

Peltan³

et al. 2006

J. Neurosci.

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The ␤-amyloid (A␤) precursor protein (APP) is cleaved sequentially by ␤-site of APP-cleaving enzyme (BACE) and ␥-secretase to release the A␤ peptides that accumulate in plaques in Alzheimer's disease (AD). GGA1, a member of the Golgi-localized ␥-ear-containing ARF-binding (GGA) protein family, interacts with BACE and influences its subcellular distribution. We now report that overexpression of GGA1 in cells increased the APP C-terminal fragment resulting from ␤-cleavage but surprisingly reduced A␤. GGA1 confined APP to the Golgi, in which fluorescence resonance energy transfer analyses suggest that the proteins come into close proximity. GGA1 blunted only APP but not notch intracellular domain release. These results suggest that GGA1 prevented APP ␤-cleavage products from becoming substrates for ␥-secretase. Direct binding of GGA1 to BACE was not required for these effects, but the integrity of the GAT (GGA1 and TOM) domain of GGA1 was. GGA1 may act as a specific spatial switch influencing APP trafficking and processing, so that APP-GGA1 interactions may have pathophysiological relevance in AD.

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“…They suggested that amyloidogenic CTFs can be produced by secretory cleavage of bAPP, which is antegradely transported through axons in human brain. Also, a 14-kDa terminal membrane-associated fragment that contains the Ab sequence was found in the optic nerve through rapid processing of bAPP (44,45).…”

Section: In Vivo Generation Of Amyloidogenic Ctfsmentioning

confidence: 99%

Pathophysiological Roles of Amyloidogenic Carboxy-Terminal Fragments of the β-Amyloid Precursor Protein in Alzheimer’s Disease

Chang

Suh

2005

J Pharmacol Sci

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Abstract. Several lines of evidence suggest that some of the neurotoxicity in Alzheimer's disease (AD) is attributed to proteolytic fragments of amyloid precursor protein (APP) and bamyloid (Ab) may not be the sole active component involved in the pathogenesis of AD. The potential effects of other cleavage products of APP need to be explored. The CTFs, carboxyterminal fragments of APP, have been found in AD patients' brain and reported to exhibit much higher neurotoxicity in a variety of preparations than Ab. Furthermore CTFs are known to impair calcium homeostasis and learning and memory through blocking LTP, triggering a strong inflammatory reaction through MAPKs-and NF-kB-dependent astrocytosis and iNOS induction. Recently, it was reported that CTF translocated into the nucleus, binding with Fe65 and CP2, and in turn, affected transcription of genes including glycogen synthase kinase-3b, which results in the induction of tau-rich neurofibrillary tangles and subsequently cell death. Spatial memory of transgenic (Tg) mice overexpressing CT100 was significantly impaired and CTFs were detected in the neurons as well as in plaques of the Tg mice and double Tg mice carrying CT100 and mutant tau. In this review, we summarize observations indicating that both CTF and Ab may participate in the neuronal degeneration in the progress of AD by differential mechanisms.

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Generation of Amyloidogenic C-terminal Fragments during Rapid Axonal Transport in Vivo of β-Amyloid Precursor Protein in the Optic Nerve

Cited by 45 publications

References 38 publications

Post-translational Processing and Turnover Kinetics of Presynaptically Targeted Amyloid Precursor Superfamily Proteins in the Central Nervous System

Post-translational Processing and Turnover Kinetics of Presynaptically Targeted Amyloid Precursor Superfamily Proteins in the Central Nervous System

GGA1 Acts as a Spatial Switch Altering Amyloid Precursor Protein Trafficking and Processing

Pathophysiological Roles of Amyloidogenic Carboxy-Terminal Fragments of the β-Amyloid Precursor Protein in Alzheimer’s Disease

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