Synaptic changes in Alzheimer’s disease and its models

Pozueta, Julio; Lefort, Roger; Shelanski, Michael L.

doi:10.1016/j.neuroscience.2012.05.050

Cited by 251 publications

(198 citation statements)

References 192 publications

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“…In turn, such changes may reproduce the phenotype of specific neurological disorders, either inflammatory or degenerative in nature, consistent with the existence of a behavioural phenotype, indicative of changes in the cerebellar function in TAG/F3 mice (Coluccia et al, 2004). These disorders may correlate with signalling pathways activation, which, in the case of Contactin 1, may concern either Notch or pCREB factors-associated pathways (Hu et al, 2003;Bizzoca et al, 2012;Puzzo et al, 2013), known to affect neural precursor proliferation/differentiation events and to be involved in either neurodegenerative or neuroinflammatory (Dragunow, 2004;Shen, 2014;Pozueta et al, 2013;Wei et al, 2011) disorders.…”

Section: Potential Significance Of Contactins Expression In Neurologimentioning

confidence: 96%

The role of Gpi-anchored axonal glycoproteins in neural development and neurological disorders

Gennarini

Bizzoca

Picocci

et al. 2017

Molecular and Cellular Neuroscience

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Section: Potential Significance Of Contactins Expression In Neurologimentioning

confidence: 96%

The role of Gpi-anchored axonal glycoproteins in neural development and neurological disorders

Gennarini

Bizzoca

Picocci

et al. 2017

Molecular and Cellular Neuroscience

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“…• AGEs-RAGE is involved in energy metabolism and mitochondrial dysfunction which effects on cognitive function and the corresponding pathological process (Kapogiannis and Mattson 2011; Leuner et al 2012; Bomba et al 2013; Caldeira et al 2013; Yang and Song 2013; Dar et al 2014).• AGEs-RAGE is a remarkable mediator of oxidative stress and inflammation which both enhance the progress of cognitive impairment(Rapoport et al 1996). • AGEs-RAGE is a promoting factor for the synaptic dysfunction and neuronal circuit dysfunction which are both the material structure of cognition, and the physiological and pathological basis of cognitionPozueta et al 2013;Steele et al 2014;Xiao et al 2014). …”

mentioning

confidence: 99%

Role of RAGE in Alzheimer’s Disease

et al. 2015

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Receptor for advanced glycation end products (RAGE) is a receptor of the immunoglobulin super family that plays various important roles under physiological and pathological conditions. Compelling evidence suggests that RAGE acts as both an inflammatory intermediary and a critical inducer of oxidative stress, underlying RAGE-induced Alzheimer-like pathophysiological changes that drive the process of Alzheimer's disease (AD). A critical role of RAGE in AD includes beta-amyloid (Aβ) production and accumulation, the formation of neurofibrillary tangles, failure of synaptic transmission, and neuronal degeneration. The steady-state level of Aβ depends on the balance between production and clearance. RAGE plays an important role in the Aβ clearance. RAGE acts as an important transporter via regulating influx of circulating Aβ into brain, whereas the efflux of brain-derived Aβ into the circulation via BBB is implemented by LRP1. RAGE could be an important contributor to Aβ generation via enhancing the activity of β- and/or γ-secretases and activating inflammatory response and oxidative stress. However, sRAGE-Aβ interactions could inhibit Aβ neurotoxicity and promote Aβ clearance from brain. Meanwhile, RAGE could be a promoting factor for the synaptic dysfunction and neuronal circuit dysfunction which are both the material structure of cognition, and the physiological and pathological basis of cognition. In addition, RAGE could be a trigger for the pathogenesis of Aβ and tau hyper-phosphorylation which both participate in the process of cognitive impairment. Preclinical and clinical studies have supported that RAGE inhibitors could be useful in the treatment of AD. Thus, an effective measure to inhibit RAGE may be a novel drug target in AD.

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“…Like in human tauopathy, another aspect of the phenotype of this model is an impairment of synaptic integrity (Pozueta, Lefort & Shelanski, 2013), for this reason, next we examined the effect of zileuton on synaptic integrity markers. Compared with the P301S control group, zileuton‐treated transgenic tau mice displayed a significant increase in the steady‐state levels of two key synaptic proteins: synaptophysin and postsynaptic density protein‐95 (PSD‐95) (Figure 4a,b).…”

Section: Resultsmentioning

confidence: 99%

Antileukotriene therapy by reducing tau phosphorylation improves synaptic integrity and cognition of P301S transgenic mice

2018

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SummaryThe 5‐lipoxygenase (5LO) is a source of inflammatory leukotrienes and is upregulated in Alzheimer's disease and related tauopathies. However, whether it directly modulates tau phosphorylation and the development of its typical neuropathology in the absence of Aβ or is a secondary event during the course of the disease pathogenesis remains to be fully elucidated. The goal of this study was to evaluate the effect that pharmacologic blockade of this inflammatory pathway has on the phenotype of a transgenic mouse model of tauopathy, the P301S mice. Starting at 3 months of age, P301S mice were randomized to receive zileuton, a specific 5LO blocker, for 7 months; then, its effect on their behavioral deficits and neuropathology was assessed. Inhibition of leukotrienes formation was associated with a reduction in tau phosphorylation and an amelioration of memory and learning as well as synaptic integrity, which were secondary to a downregulation of the cdk5 kinase pathway. Our results demonstrate that the 5LO enzyme is a key player in modulating tau phosphorylation and pathology and that blockade of its enzymatic activity represents a desirable disease‐modifying therapeutic approach for tauopathy.

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Synaptic changes in Alzheimer’s disease and its models

Cited by 251 publications

References 192 publications

The role of Gpi-anchored axonal glycoproteins in neural development and neurological disorders

The role of Gpi-anchored axonal glycoproteins in neural development and neurological disorders

Role of RAGE in Alzheimer’s Disease

Antileukotriene therapy by reducing tau phosphorylation improves synaptic integrity and cognition of P301S transgenic mice

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