Amyloid Precursor Protein Is Trafficked and Secreted via Synaptic Vesicles

Groemer, Teja W.; Thiel, Cora S.; Holt, Matthew; Riedel, Dietmar; Hua, Yunfeng; Hüve, Jana; Wilhelm, Benjamin G.; Klingauf, Jürgen

doi:10.1371/journal.pone.0018754

Cited by 91 publications

(87 citation statements)

References 61 publications

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“…After trypsin digestion and enrichment on Neutravidin agarose, the SNO-peptides were analyzed by LC-MS/MS using in house developed MSparky software. (72,73). Parallel functional analyses using KEGG pathways supported the finding that proteins in the S-nitroso-diff set are linked to axon guidance and regulation of actin cytoskeleton (p ϭ 3.71E-02, Fig.…”

Section: Differentially S-nitrosylated Proteins In Happ Mouse Brain Amentioning

confidence: 53%

Global Analysis of S-nitrosylation Sites in the Wild Type (APP) Transgenic Mouse Brain-Clues for Synaptic Pathology

Zaręba-Kozioł

Szwajda

Dadlez

et al. 2014

Molecular & Cellular Proteomics

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Section: Differentially S-nitrosylated Proteins In Happ Mouse Brain Amentioning

confidence: 53%

Global Analysis of S-nitrosylation Sites in the Wild Type (APP) Transgenic Mouse Brain-Clues for Synaptic Pathology

Zaręba-Kozioł

Szwajda

Dadlez

et al. 2014

Molecular & Cellular Proteomics

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“…During necrotic neuronal death, a loss of all cell membranes integrity was finally noted [49,50]. Amyloid-␤ protein precursor is present in large quantities in all cell membranes [51], and, in the above situation, there may be an excess of protease substrate, which is the amyloid-␤ protein precursor. Loss of membrane integrity allows necrotic cells the ability to trigger an amyloid-␤ protein precursor uncontrolled release and metabolism [52].…”

Section: Discussionmentioning

confidence: 99%

Discrepancy in Expression of β-Secretase and Amyloid-β Protein Precursor in Alzheimer-Related Genes in the Rat Medial Temporal Lobe Cortex Following Transient Global Brain Ischemia

Pluta

Kocki

Ułamek-Kozioł³

et al. 2016

JAD

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Abstract. Brain ischemia may be causally related with Alzheimer's disease. Presumably, ␤-secretase and amyloid-␤ protein precursor gene expression changes may be associated with Alzheimer's disease neuropathology. Consequently, we have examined quantitative changes in both ␤-secretase and amyloid-␤ protein precursor genes in the medial temporal lobe cortex with the use of quantitative rtPCR analysis following 10-min global brain ischemia in rats with survival of 2, 7, and 30 days. The greatest significant overexpression of ␤-secretase gene was noted on the 2nd day, while on days 7-30 the expression of this gene was only modestly downregulated. Amyloid-␤ protein precursor gene was downregulated on the 2nd day, but on days 7-30 postischemia, there was a significant reverse tendency. Thus, the demonstrated alterations indicate that the considerable changes of expression of ␤-secretase and amyloid-␤ protein precursor genes may be connected with a response of neurons in medial temporal lobe cortex to transient global brain ischemia. Finally, the ischemia-induced gene changes may play a key role in a late and slow onset of Alzheimer-type pathology.

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“…19,109 Furthermore, several studies have provided experimental evidence that traumatic head injury in rodents and humans can result in significant elevation in APP levels, 110,111 as well as Aβ generation and amyloid plaque deposition. 112,113 In line with the high turnover, rapid anterograde transport, and processing of APP in distal compartments, [114][115][116] genetically induced fibre tract degeneration in the gracile axonal dystrophy mouse provokes rapid axonal accumulation of APP and Aβ. 117 Moreover, disruption of axonal and dendritic transport following impaired lysosomal proteolysis is accompanied by increased levels of C-terminally cleaved APP fragments, 118 which indicates that a combination of increased synthesis and impaired axonal transport of APP induces its rapid accumulation in neurites with subsequent aberrant cleavage.…”

Section: Inflammation and Cellular Stressmentioning

confidence: 98%

Deciphering the mechanism underlying late-onset Alzheimer disease

2012

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Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-(A) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between A and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of A accumulation in late-onset AD. Abstract | Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence ...

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Amyloid Precursor Protein Is Trafficked and Secreted via Synaptic Vesicles

Cited by 91 publications

References 61 publications

Global Analysis of S-nitrosylation Sites in the Wild Type (APP) Transgenic Mouse Brain-Clues for Synaptic Pathology

Global Analysis of S-nitrosylation Sites in the Wild Type (APP) Transgenic Mouse Brain-Clues for Synaptic Pathology

Discrepancy in Expression of β-Secretase and Amyloid-β Protein Precursor in Alzheimer-Related Genes in the Rat Medial Temporal Lobe Cortex Following Transient Global Brain Ischemia

Deciphering the mechanism underlying late-onset Alzheimer disease

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