β-Amyloid treatment of two complementary P301L tau-expressing Alzheimer's disease models reveals similar deregulated cellular processes

David, Della; Ittner, Lars M.; Gehrig, Peter; Nergenau, Denise; Shepherd, Claire E.; Halliday, Glenda M.; Gotz, Juergen

doi:10.1002/pmic.200600634

Cited by 62 publications

(52 citation statements)

References 45 publications

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“…Tissue embedding was done in paraffin in a Shandon Excelsior processor (Thermo). Human AD and control tissue was obtained through the Australian Brain Bank Program as described (10). Immunohistochemistry on 3-m sections has been described in detail before (34).…”

Section: Methodsmentioning

confidence: 99%

Phosphorylated Tau Interacts with c-Jun N-terminal Kinase-interacting Protein 1 (JIP1) in Alzheimer Disease

Ittner

Götz

2009

Journal of Biological Chemistry

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137

102

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In Alzheimer disease (AD) and frontotemporal dementia the microtubule-associated protein Tau becomes progressively hyperphosphorylated, eventually forming aggregates. However, how Tau dysfunction is associated with functional impairment is only partly understood, especially at early stages when Tau is mislocalized but has not yet formed aggregates. Impaired axonal transport has been proposed as a potential pathomechanism, based on cellular Tau models and Tau transgenic mice. We recently reported K369I mutant Tau transgenic K3 mice with axonal transport defects that suggested a cargo-selective impairment of kinesin-driven anterograde transport by Tau. Here, we show that kinesin motor complex formation is disturbed in the K3 mice. We show that under pathological conditions hyperphosphorylated Tau interacts with c-Jun N-terminal kinase-interacting protein 1 (JIP1), which is associated with the kinesin motor protein complex. As a result, transport of JIP1 into the axon is impaired, causing JIP1 to accumulate in the cell body. Because we found trapping of JIP1 and a pathological Tau/ JIP1 interaction also in AD brain, this may have pathomechanistic implications in diseases with a Tau pathology. This is supported by JIP1 sequestration in the cell body of Tau-transfected primary neuronal cultures. The pathological Tau/JIP1 interaction requires phosphorylation of Tau, and Tau competes with the physiological binding of JIP1 to kinesin light chain. Because JIP1 is involved in regulating cargo binding to kinesin motors, our findings may, at least in part, explain how hyperphosphorylated Tau mediates impaired axonal transport in AD and frontotemporal dementia.

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Section: Methodsmentioning

confidence: 99%

Phosphorylated Tau Interacts with c-Jun N-terminal Kinase-interacting Protein 1 (JIP1) in Alzheimer Disease

Ittner

Götz

2009

Journal of Biological Chemistry

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137

102

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“…In determining the role of distinct proteins in these processes, traditionally, candidate-driven approaches have been pursued, linking neuronal dysfunction to the distribution of known proteins in healthy compared with degenerating neurons, or in transgenic compared with control brain. In comparison, proteomics offers a powerful nonbiased approach as shown by us previously (4,5).…”

mentioning

confidence: 99%

Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice

Rhein

Song

Wiesner

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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588

460

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Alzheimer's disease (AD) is characterized by amyloid-beta (A␤)-containing plaques, neurofibrillary tangles, and neuron and synapse loss. Tangle formation has been reproduced in P301L tau transgenic pR5 mice, whereas APP sw PS2 N141I double-transgenic APP152 mice develop A␤ plaques. Cross-breeding generates triple transgenic ( triple AD) mice that combine both pathologies in one model. To determine functional consequences of the combined A␤ and tau pathologies, we performed a proteomic analysis followed by functional validation. Specifically, we obtained vesicular preparations from triple AD mice, the parental strains, and nontransgenic mice, followed by the quantitative mass-tag labeling proteomic technique iTRAQ and mass spectrometry. Within 1,275 quantified proteins, we found a massive deregulation of 24 proteins, of which one-third were mitochondrial proteins mainly related to complexes I and IV of the oxidative phosphorylation system (OXPHOS). Notably, deregulation of complex I was tau dependent, whereas deregulation of complex IV was A␤ dependent, both at the protein and activity levels. Synergistic effects of A␤ and tau were evident in 8-month-old triple AD mice as only they showed a reduction of the mitochondrial membrane potential at this early age. At the age of 12 months, the strongest defects on OXPHOS, synthesis of ATP, and reactive oxygen species were exhibited in the triple AD mice, again emphasizing synergistic, age-associated effects of A␤ and tau in perishing mitochondria. Our study establishes a molecular link between A␤ and tau protein in AD pathology in vivo, illustrating the potential of quantitative proteomics.amyloid-beta peptide ͉ electron transport chain ͉ energy metabolism ͉ mitochondrial complexes ͉ tau protein A lzheimer's disease (AD) is a devastating neurodegenerative disorder affecting Ͼ15 million people worldwide (1). The key histopathological features are amyloid-beta (A␤)-containing plaques and microtubule-associated protein tau-containing neurofibrillary tangles (NFTs), along with neuronal and synapse loss in selected brain areas (2, 3). In determining the role of distinct proteins in these processes, traditionally, candidate-driven approaches have been pursued, linking neuronal dysfunction to the distribution of known proteins in healthy compared with degenerating neurons, or in transgenic compared with control brain. In comparison, proteomics offers a powerful nonbiased approach as shown by us previously (4, 5).APP152 (APP/PS2) double-transgenic mice model the A␤ plaque pathology of AD (6); they coexpress the N141I mutant form of PS2 together with the APP sw mutant found in familial cases of AD. The mice display age-related cognitive deficits associated with discrete brain A␤ deposition and inflammation (6). pR5 mice model the tangle pathology of AD (7-9). They express P301L mutant tau found in familial cases of frontotemporal dementia (FTD), a dementia related to AD. The pR5 mice show a hippocampus-and amygdala-dependent behavioral impairment related to AD (10). Crossing of ...

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“…In Table 3 a comparison between the protein identified in our study and the proteins identified in other studies is shown, indicating that there is a general response of cells to toxic aggregates that is not sequence specific [12,13,30,31,32]. Actually, changes in the expression levels of Gapdh, actin, tubulin and heat shock proteins have frequently been reported in amyloid-linked proteomic studies possibly because they are related to a generic response to stress conditions [33] such as that associated with the growth of amyloid aggregates.…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of cells exposed to prefibrillar aggregates of HypF-N

Magherini

Pieri

Guidi

et al. 2009

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Several human diseases are associated with the deposition of stable ordered protein aggregates known as amyloid fibrils. In addition, a large wealth of data shows that proteins not involved in amyloidoses, are able to form, in vitro, amyloid-like prefibrillar and fibrillar assemblies indistinguishable from those grown from proteins associated with disease. Previous studies showed that early prefibrillar aggregates of the N-terminal domain of the prokaryotic hydrogenase maturation factor HypF (HypF-N) are cytotoxic, inducing early mitochondria membrane depolarization, activation of caspase 9 and eventually cell death. To gain knowledge on the molecular basis of HypF-N aggregate cytotoxicity, we performed a differential proteomic analysis of NIH-3T3 cells exposed to HypF-N prefibrillar aggregates in comparison with control cells. Two-dimensional gel electrophoresis followed by protein identification by MALDI-TOF MS, allowed us to identify 21 proteins differentially expressed. The changes of the expression level of proteins involved in stress response (Hsp60 and 78 kDa glucose-regulated protein) and in signal transduction (Focal adhesion kinase1) appear particularly interesting as possible determinants of the cell fate. The levels of some of the differently expressed proteins were modified also in similar studies carried out on cells exposed to Aβ or α-synuclein aggregates, supporting the existence of shared features of amyloid cytotoxicity.

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β-Amyloid treatment of two complementary P301L tau-expressing Alzheimer's disease models reveals similar deregulated cellular processes

Cited by 62 publications

References 45 publications

Phosphorylated Tau Interacts with c-Jun N-terminal Kinase-interacting Protein 1 (JIP1) in Alzheimer Disease

Phosphorylated Tau Interacts with c-Jun N-terminal Kinase-interacting Protein 1 (JIP1) in Alzheimer Disease

Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice

Proteomic analysis of cells exposed to prefibrillar aggregates of HypF-N

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