Tau protein directly interacts with the amyloid β-protein precursor: Implications for Alzheimer's disease

Smith, Mark A.; Siedlak, Sandra L.; Richey, Peggy L.; Mulvihill, Paul; Ghiso, Jorge; Frangione, Blas; Tagliavini, Fabrizio; Giaccone, Giorgio; Bugiani, Orso; Praprotnik, Darja; Kalaria, Rajesh N.; Perry, George

doi:10.1038/nm0495-365

Cited by 78 publications

(44 citation statements)

References 31 publications

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“…This distinction between APP and Aβ is important in understanding the molecular pathway of AD. It has previously been shown that tau binds to APP [16], and we showed that tau is necessary for the trafficking of APP to the neuronal surface [11]. In this role, tau facilitates the export of iron as APP stabilizes surface ferroportin, which is the obligate iron export protein [11].…”

Section: Introductionmentioning

confidence: 58%

Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau

Lei

Tuo

et al. 2015

Neurotherapeutics

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The amyloid cascade hypothesis of Alzheimer's disease (AD) positions tau protein as a downstream mediator of β-amyloid (Aβ) toxicity This is largely based on genetic cross breeding, which showed that tau ablation in young (3-7-month-old) transgenic mice overexpressing mutant amyloid precursor protein (APP) abolished the phenotype of the APP AD model. This evidence is complicated by the uncertain impact of overexpressing mutant APP, rather than Aβ alone, and for potential interactions between tau and overexpressed APP. Cortical iron elevation is also implicated in AD, and tau promotes iron export by trafficking APP to the neuronal surface. Here, we utilized an alternative model of Aβ toxicity by directly injecting Aβ oligomers into the hippocampus of young and old wild-type and tau knockout mice. We found that ablation of tau protected against Aβ-induced cognitive impairment, hippocampal neuron loss, and iron accumulation. Despite injected human Aβ being eliminated after 5 weeks, enduring changes, including increased APP levels, tau reduction, tau phosphorylation, and iron accumulation, were observed. While the results from our study support the amyloid cascade hypothesis, they also suggest that downstream effectors of Aβ, which propagate toxicity after Aβ has been cleared, may be tractable therapeutic targets.

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Section: Introductionmentioning

confidence: 58%

Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau

Lei

Tuo

et al. 2015

Neurotherapeutics

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“…Moreover, APP transport was shown to be impaired by elevated tau, suggesting a possible link of the 2 proteins (28,29). Oligomeric A␤ can attach to tau (30,31), causing a rapid dissociation of tau from microtubules and a collapse of axonal structures leading initially to synaptic malfunction and ultimately, neuronal death. Interestingly, A␤ may not only be located to the cell surface but also directly interact with mitochondria (20) as it can be imported into mitochondria via the translocase of the outer membrane (TOM) machinery (32).…”

Section: Discussionmentioning

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.

597

486

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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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“…Aβ may induce the phosphorylation of tau by: (a) directly interacting with a domain of APP (714-723) [47,125], (b) by inducing tau protein kinase I and subsequently, tau proteins recognised by the antibody Alz-50 [132], (c) as a result of synergisms between Aβ and tau [100,101], or (d) by directly altering the phosphorylated state of tau [23].…”

Section: Key Observations In the Development Of The Amyloid Cascade Hmentioning

confidence: 99%

A critical analysis of the ‘amyloid cascade hypothesis’

Armstrong¹

2014

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A b s t r a c t The 'amyloid cascade hypothesis' (ACH) is the most influential model of the pathogenesis of Alzheimer's disease (AD). The hypothesis proposes that the deposition of β-amyloid (Aβ) is the initial pathological event in AD, leading to the formation of extracellular senile plaques (SP), tau-immunoreactive neurofibrillary tangles (NFT), neuronal loss, and ultimately, clinical dementia. Ever since the formulation of the ACH, however, there have been questions regarding whether it completely describes AD pathogenesis. This review critically examines various aspects of the ACH including its origin and development, the role of amyloid precursor protein (APP), whether SP and NFT are related to the development of clinical dementia, whether Aβ and tau are 'reactive' proteins, and whether there is a pathogenic relationship between SP and NFT. The results of transgenic experiments and treatments for AD designed on the basis of the ACH are also reviewed. It was concluded: (1) Aβ and tau could be the products rather than the cause of neurodegeneration in AD, (2) it is doubtful whether there is a direct causal link between Aβ and tau, and (3) SP and NFT may not be directly related to the development of dementia, (4) transgenic models involving

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Tau protein directly interacts with the amyloid β-protein precursor: Implications for Alzheimer's disease

Cited by 78 publications

References 31 publications

Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau

Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau

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

A critical analysis of the ‘amyloid cascade hypothesis’

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