Aβ and tau toxicities in Alzheimer’s are linked via oxidative stress-induced p38 activation: Protective role of vitamin E

2014

AbstractOxidative stress is a hallmark of Alzheimer’s disease (AD). We propose that rather than causing damage because of the action of free radicals, oxidative stress deranges signaling pathways leading to tau hyperphosphorylation, a hallmark of the disease. Indeed, incubation of neurons in culture with 5 µM beta-amyloid peptide (Aβ) causes an activation of p38 MAPK (p38) that leads to tau hyperphosphorylation. Inhibition of p38 prevents Aβ-induced tau phosphorylation. Aβ-induced effects are prevented when neurons are co-incubated with trolox (the water-soluble analog of vitamin E).We have confirmed these results in vivo, in APP/PS1 double transgenic mice of AD. We have found that APP/PS1 …

Oxidative Stress And Ubiquitin Ligases: Their Involvement In Alzheimer’s Disease Pathophysiology

2015

Oxidative stress is a major hallmark in Alzheimer’s Disease. We showed that amyloid beta (Aβ 1-42 ), induces mitochondrial oxidative stress. We focused on dysregulations of ubiquitin ligases in Alzheimer’s and their relation to oxidative stress. The anaphase-promoting complex/cyclosome (APC/C)-Cdh1 ubiquitin ligase has a role as cell cycle regulator in proliferating cells and, recently another role in the regulation the degradation of key glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase-3 has been found (Almeida et al., 2012). Herrero-Mendez et al. observed in 2009 that inhibition of Cdh1 leads to an upregulation of Pfkfb3 in neurons and that this results in the activ…

New Functions of APC/C Ubiquitin Ligase in the Nervous System and Its Role in Alzheimer’s Disease

2017

The E3 ubiquitin ligase Anaphase Promoting Complex/Cyclosome (APC/C) regulates important processes in cells, such as the cell cycle, by targeting a set of substrates for degradation. In the last decade, APC/C has been related to several major functions in the nervous system, including axon guidance, synaptic plasticity, neurogenesis, and neuronal survival. Interestingly, some of the identified APC/C substrates have been related to neurodegenerative diseases. There is an accumulation of some degradation targets of APC/C in Alzheimer’s disease (AD) brains, which suggests a dysregulation of the protein complex in the disorder. Moreover, recently evidence has been provided for an inactivation o…

Reductive Stress: A New Concept in Alzheimer's Disease

2015

Reactive oxygen species play a physiological role in cell signaling and also a pathological role in diseases, when antioxidant defenses are overwhelmed causing oxidative stress. However, in this review we will focus on reductive stress that may be defined as a pathophysiological situation in which the cell becomes more reduced than in the normal, resting state. This may occur in hypoxia and also in several diseases in which a small but persistent generation of oxidants results in a hormetic overexpression of antioxidant enzymes that leads to a reduction in cell compartments. This is the case of Alzheimer's disease. Individuals at high risk of Alzheimer's (because they carry the ApoE4 allele…

Oral Monosodium Glutamate Administration Causes Early Onset of Alzheimer's Disease-Like Pathophysiology in APP/PS1 Mice.

2019

Glutamate excitotoxicity has long been related to Alzheimer's disease (AD) pathophysiology, and it has been shown to affect the major AD-related hallmarks, amyloid-β peptide (Aβ) accumulation and tau phosphorylation (p-tau). We investigated whether oral administration of monosodium glutamate (MSG) has effects in a murine model of AD, the double transgenic mice APP/PS1. We found that AD pathogenic factors appear earlier in APP/PS1 when supplemented with MSG, while wildtype mice were essentially not affected. Aβ and p-tau levels were increased in the hippocampus in young APP/PS1 animals upon MSG administration. This was correlated with increased Cdk5-p25 levels. Furthermore, in these mice, we…

Excitotoxicity in AD is partially caused by the inactivation of APC/C-Cdh1 E3 Ubiquitin Ligase

2013

Increased basal antioxidant levels in RCAN1 - deficient mice lowers oxidative injury after acute paraquat insult.

2020

RCAN1 is an inhibitor of the phosphatase calcineurin, which is involved in the regulation of oxidative stress and apoptosis, among other important cell processes. Here we have used RCAN1 deficient mice (RCAN1-/-) to elucidate its role after an acute oxidative insult such as paraquat injection. We have observed that RCAN1-/- mice show less oxidative damage than wildtype (WT) mice after treatment. Under basal conditions, RCAN1-/- animals express more calcineurin, heme oxygenase-1, Nrf2, and catalase compared to WT mice (controls). This may explain the less severe effect of paraquat treatment on RCAN1-/- mice compared to WT. We showed that oxidative stress is involved in the early stages of ap…

Aβ Induces Excitotoxicity Mediated by APC/C-Cdh1 Depletion That Can Be Prevented by Glutaminase Inhibition Promoting Neuronal Survival

2016

AbstractThe E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) is activated by the fizzy-related protein homolog/CDC20-like protein 1 (cdh1) in post-mitotic neurons. Growing evidence suggests that dysregulation of APC/C-Cdh1 is involved in neurodegenerative diseases. Here we show in neurons that oligomers of amyloid beta (Aβ), a peptide related to Alzheimer’s disease, cause proteasome-dependent degradation of cdh1. This leads to a subsequent increase in glutaminase (a degradation target of APC/C-Cdh1), which causes an elevation of glutamate levels and further intraneuronal Ca2+ dysregulation, resulting in neuronal apoptosis. Glutaminase inhibition prevents glutamate excitotoxi…

Molecular mechanisms linking amyloid β toxicity and Tau hyperphosphorylation in Alzheimer׳s disease

2015

Neurofibrillary tangles (aggregates of cytoskeletal Tau protein) and senile plaques (aggregates mainly formed by amyloid β peptide) are two landmark lesions in Alzheimer׳s disease. Some researchers have proposed tangles, whereas others have proposed plaques, as primary lesions. For a long time, these were thought of as independent mechanisms. However, experimental evidence suggests that both lesions are intimately related. We review here some molecular pathways linking amyloid β and Tau toxicities involving, among others, glycogen synthase kinase 3β, p38, Pin1, cyclin-dependent kinase 5, and regulator of calcineurin 1. Understanding amyloid β and Tau toxicities as part of a common pathophys…

P4‐256: POSITIVE FEEDBACK LOOP OF APC/C‐CDH1‐MEDIATED EXCITOTOXICITY IN ALZHEIMER'S DISEASE

2014

The Role of APC/C-Cdh1 in Alzheimer's disease

2016

Alzheimer’s disease (AD) is the most common cause of dementia among elderly individuals above 65 years. Estimations suggest that there are currently about 47.5 million people worldwide suffering from dementia, of which 60-70% are AD cases (World Health Organization, 2015). It is an irreversible disease of progressive nature, which leads to deterioration in cognitive functions beyond what is normal in a healthy aging process. Among the affected cognitive functions are memory, thinking skills and orientation. AD is one of the major causes of disability among older people and has a big impact on socio-economical capacities. There is currently no treatment to cure AD and it is a very active fie…