Poly-ubiquitin profile in Alzheimer disease brain

Tramutola, Antonella; Triani, Francesca; Domenico, Fabio Di; Barone, Eugenio; Cai, Jian; Klein, Jon B.; Perluigi, Marzia; Butterfield, D. Allan

doi:10.1016/j.nbd.2018.07.006

Cited by 31 publications

(18 citation statements)

References 57 publications

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“…We showed, in the frontal cortex from DS individuals before and after development of AD neuropathology, that key components of the PQC are irreversibly oxidatively modified resulting in aberrant protein functionality [ 7 , 9 ]. In agreement, we observed, in young DS subjects, the early accumulation of polyubiquitinylated proteins before the appearance of AD symptoms [ 10 , 11 ]. These data suggest that impairment of protein degradative system may play a crucial role in the early accumulation of amyloid beta (Aβ) and tau toxic protein aggregates, thus accelerating the neurodegenerative process.…”

Section: Introductionsupporting

confidence: 79%

Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome

Tramutola

Lanzillotta

Barone

et al. 2018

Transl Neurodegener

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BackgroundDown syndrome (DS) individuals, by the age of 40s, are at increased risk to develop Alzheimer-like dementia, with deposition in brain of senile plaques and neurofibrillary tangles. Our laboratory recently demonstrated the disturbance of PI3K/AKT/mTOR axis in DS brain, prior and after the development of Alzheimer Disease (AD). The aberrant modulation of the mTOR signalling in DS and AD age-related cognitive decline affects crucial neuronal pathways, including insulin signaling and autophagy, involved in pathology onset and progression. Within this context, the therapeutic use of mTOR-inhibitors may prevent/attenuate the neurodegenerative phenomena. By our work we aimed to rescue mTOR signalling in DS mice by a novel rapamycin intranasal administration protocol (InRapa) that maximizes brain delivery and reduce systemic side effects.MethodsTs65Dn mice were administered with InRapa for 12 weeks, starting at 6 months of age demonstrating, at the end of the treatment by radial arms maze and novel object recognition testing, rescued cognition.ResultsThe analysis of mTOR signalling, after InRapa, demonstrated in Ts65Dn mice hippocampus the inhibition of mTOR (reduced to physiological levels), which led, through the rescue of autophagy and insulin signalling, to reduced APP levels, APP processing and APP metabolites production, as well as, to reduced tau hyperphosphorylation. In addition, a reduction of oxidative stress markers was also observed.DiscussionThese findings demonstrate that chronic InRapa administration is able to exert a neuroprotective effect on Ts65Dn hippocampus by reducing AD pathological hallmarks and by restoring protein homeostasis, thus ultimately resulting in improved cognition. Results are discussed in term of a potential novel targeted therapeutic approach to reduce cognitive decline and AD-like neuropathology in DS individuals.Electronic supplementary materialThe online version of this article (10.1186/s40035-018-0133-9) contains supplementary material, which is available to authorized users.

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Section: Introductionsupporting

confidence: 79%

Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome

Tramutola

Lanzillotta

Barone

et al. 2018

Transl Neurodegener

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“…Our results provide a basis for pharmacological manipulation of AMPAR acetylation as a potential therapeutic strategy. On a broader level, because ubiquitination, a modulation antagonizing acetylation and resulting in receptor degradation, is enhanced in AD ( Gadhave et al., 2016 ; Liu et al., 2019 ; Tramutola et al., 2018 ), manipulation of both of these opposing processes should be considered for more efficient management of AD.…”

Section: Discussionmentioning

confidence: 99%

Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease

et al. 2020

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Summary In Alzheimer's disease (AD), decreases in the amount and synaptic localization of AMPA receptors (AMPARs) result in weakened synaptic activity and dysfunction in synaptic plasticity, leading to impairments in cognitive functions. We have previously found that AMPARs are subject to lysine acetylation, resulting in higher AMPAR stability and protein accumulation. Here we report that AMPAR acetylation was significantly reduced in AD and neurons with Aβ incubation. We identified p300 as the acetyltransferase responsible for AMPAR acetylation and found that enhancing GluA1 acetylation ameliorated Aβ-induced reductions in total and cell-surface AMPARs. Importantly, expression of acetylation mimetic GluA1 (GluA1-4KQ) in APP/PS1 mice rescued impairments in synaptic plasticity and memory. These findings indicate that Aβ-induced reduction in AMPAR acetylation and stability contributes to synaptopathy and memory deficiency in AD, suggesting that AMPAR acetylation may be an effective molecular target for AD therapeutics.

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“…Notably, Pin1 is modified by oxidation, leading to the loss of its activity in the hippocampus in AD (Butterfield et al, 2006;Sultana et al, 2006). Besides, oxidized Pin1 may be recognized by the ubiquitinylation system, giving rise to the polyubiquitination (Tramutola et al, 2018). By employing antibodies specifically recognizing oxidized C113 of Pin1, Pin1 oxidation on C113 has been identified to inactivate the catalytic activity of Pin1, and C113-oxidized Pin1 is elevated in human AD brains compared with age-matched controls (Chen et al, 2015).…”

Section: Pin1 Post-translational Modification In Admentioning

confidence: 99%

Peptidyl-Prolyl Cis/Trans Isomerase Pin1 and Alzheimer’s Disease

Wang

Zhou

Chen

et al. 2020

Front. Cell Dev. Biol.

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Alzheimer's disease (AD) is the most common cause of dementia with cognitive decline. The neuropathology of AD is characterized by intracellular aggregation of neurofibrillary tangles consisting of hyperphosphorylated tau and extracellular deposition of senile plaques composed of beta-amyloid peptides derived from amyloid precursor protein (APP). The peptidyl-prolyl cis/trans isomerase Pin1 binds to phosphorylated serine or threonine residues preceding proline and regulates the biological functions of its substrates. Although Pin1 is tightly regulated under physiological conditions, Pin1 deregulation in the brain contributes to the development of neurodegenerative diseases, including AD. In this review, we discuss the expression and regulatory mechanisms of Pin1 in AD. We also focus on the molecular mechanisms by which Pin1 controls two major proteins, tau and APP, after phosphorylation and their signaling cascades. Moreover, the major impact of Pin1 deregulation on the progression of AD in animal models is discussed. This information will lead to a better understanding of Pin1 signaling pathways in the brain and may provide therapeutic options for the treatment of AD.

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Poly-ubiquitin profile in Alzheimer disease brain

Cited by 31 publications

References 57 publications

Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome

Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome

Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease

Peptidyl-Prolyl Cis/Trans Isomerase Pin1 and Alzheimer’s Disease

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