Rodent Aβ Modulates the Solubility and Distribution of Amyloid Deposits in Transgenic Mice

Jankowsky, Joanna L.; Younkin, Linda H.; Gonzales, Victoria; Fadale, Daniel J.; Slunt, Hilda H.; Lester, Henry A.; Younkin, Steven G.; Borchelt, David R.

doi:10.1074/jbc.m611050200

Cited by 104 publications

(94 citation statements)

References 56 publications

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“…We found no evidence for endogenous mouse Aβ aggregation in the human Aβ injection model (Figs. 4a, b and 7a), consistent with previous findings [36,37].…”

Section: Discussionsupporting

confidence: 92%

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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“…We found no evidence for endogenous mouse Aβ aggregation in the human Aβ injection model (Figs. 4a, b and 7a), consistent with previous findings [36,37].…”

Section: Discussionsupporting

confidence: 92%

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 possible presence of APP would not be surprising because it is several times up-regulated in this animal model. Lower A␤ molecular weight forms were not detected using anti-A␤ (6E10), as reported previously (41).…”

Section: Gpbp Is Present In Brain Amyloidsupporting

confidence: 83%

Goodpasture Antigen-binding Protein/Ceramide Transporter Binds to Human Serum Amyloid P-Component and Is Present in Brain Amyloid Plaques

Mencarelli

Bode

Losen

et al. 2012

Journal of Biological Chemistry

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Background:The Goodpasture antigen-binding protein (GPBP) and serum amyloid P component (SAP) bind to type IV collagen and are found in plasma. Results: GPBP binds to human SAP. Conclusion: GPBP and SAP form complexes under physiological and pathological conditions. Significance: This interaction might be involved in protein aggregation in Alzheimer disease and the resulting innate immune response.

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“…Cellular Aggregation Assays-For filter trap assays, PC12 cells were solubilized in Triton-based lysis buffer, briefly sonicated for three 1-s pulses to shear DNA as previously described (20,(41)(42)(43)(44), and centrifuged at 16,000 ϫ g for 30 min to remove cellular debris. Supernatants were spotted onto a cellulose acetate membrane (0.22-m pore size) in a dot blot apparatus attached to a vacuum source.…”

Section: Journal Of Biological Chemistry 35691mentioning

confidence: 99%

Ubiquilin-1 Is a Molecular Chaperone for the Amyloid Precursor Protein

Stieren

Ayadi

Xiao

et al. 2011

Journal of Biological Chemistry

109

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Alzheimer disease (AD) is associated with extracellular deposition of proteolytic fragments of amyloid precursor protein (APP). Although mutations in APP and proteases that mediate its processing are known to result in familial, early onset forms of AD, the mechanisms underlying the more common sporadic, yet genetically complex forms of the disease are still unclear. Four single-nucleotide polymorphisms within the ubiquilin-1 gene have been shown to be genetically associated with AD, implicating its gene product in the pathogenesis of late onset AD. However, genetic linkage between ubiquilin-1 and AD has not been confirmed in studies examining different populations. Here we show that regardless of genotype, ubiquilin-1 protein levels are significantly decreased in late onset AD patient brains, suggesting that diminished ubiquilin function may be a common denominator in AD progression. Our interrogation of putative ubiquilin-1 activities based on sequence similarities to proteins involved in cellular quality control showed that ubiquilin-1 can be biochemically defined as a bona fide molecular chaperone and that this activity is capable of preventing the aggregation of amyloid precursor protein both in vitro and in live neurons. Furthermore, we show that reduced activity of ubiquilin-1 results in augmented production of pathogenic amyloid precursor protein fragments as well as increased neuronal death. Our results support the notion that ubiquilin-1 chaperone activity is necessary to regulate the production of APP and its fragments and that diminished ubiquilin-1 levels may contribute to AD pathogenesis.

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Rodent Aβ Modulates the Solubility and Distribution of Amyloid Deposits in Transgenic Mice

Cited by 104 publications

References 56 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

Goodpasture Antigen-binding Protein/Ceramide Transporter Binds to Human Serum Amyloid P-Component and Is Present in Brain Amyloid Plaques

Ubiquilin-1 Is a Molecular Chaperone for the Amyloid Precursor Protein

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