Alzheimer's disease, β‐amyloid, glutamate, NMDA receptors and memantine – searching for the connections

Danysz, Wojciech; Parsons, Chris G.

doi:10.1111/j.1476-5381.2012.02057.x

Cited by 431 publications

(319 citation statements)

References 257 publications

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“…Aβ has been shown to bind to postsynaptic receptors, such as α7-nicotinic acetylcholine receptor (α7nAChR) (7), receptor for advanced glycation end products (RAGE) (8), receptor tyrosine kinase EPHB2 (9), and cellular prion protein PrP C (10). These "Aβ receptors," except for RAGE, have been reported to mediate toxicity of Aβ oligomers through modulating NMDA receptors (NMDAR) (11). Aβ oligomers, including dimers from AD brains (12,13), dodecamers (Aβ*56) from AD model mice (14), and in vitro-generated Aβ-derived diffusible ligands (ADDLs) (15,16), induce synaptic impairment by affecting NMDAR (11).…”

mentioning

confidence: 99%

Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

Ohnishi

Yanazawa

Sasahara

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

117

155

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Neurodegeneration correlates with Alzheimer's disease (AD) symptoms, but the molecular identities of pathogenic amyloid β-protein (Aβ) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10-to 15-nm spherical Aβ oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuronspecific Na + /K + -ATPase α3 subunit (NAKα3). ASPD-binding to NAKα3 impaired NAKα3-specific activity, activated N-type voltage-gated calcium channels, and caused mitochondrial calcium dyshomeostasis, tau abnormalities, and neurodegeneration. NMR and molecular modeling studies suggested that spherical ASPD contain N-terminal-Aβ-derived "thorns" responsible for target binding, which are distinct from low molecular-weight oligomers and dodecamers. The fourth extracellular loop (Ex4) region of NAKα3 encompassing Asn 879 and Trp 880 is essential for ASPD-NAKα3 interaction, because tetrapeptides mimicking this Ex4 region bound to the ASPD surface and blocked ASPD neurotoxicity. Our findings open up new possibilities for knowledge-based design of peptidomimetics that inhibit neurodegeneration in AD by blocking aberrant ASPD-NAKα3 interaction.NMR | computational modeling | abnormal protein-protein interaction in synapse | hyperexcitotoxicity | protein-protein interaction inhibitors

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mentioning

confidence: 99%

Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

Ohnishi

Yanazawa

Sasahara

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

117

155

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“…Two possible connections are depicted in this scheme. Thus, Aß accumulation leads to an increased calcium flux through NMDAR and thus triggers both the CAMKK and the ERK1/2 mediated activation of AMPK [40]. While Ca 2+ concentration and Aß accumulation are interdependent, the latter is prevented by the action of AMPK [41] and by the deacetylase SIRT1 [42].…”

Section: Posttranslational Modifications Influencing Tau Toxicitymentioning

confidence: 99%

Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

Heinisch¹,

Brandt²

2016

MIC

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In the past decade, yeast have been frequently employed to study the molecular mechanisms of human neurodegenerative diseases, generally by means of heterologous expression of genes encoding the relevant hallmark proteins. However, it has become evident that substantial posttranslational modifications of many of these proteins are required for the development and progression of potentially disease relevant changes. This is exemplified by the neuronal tau proteins, which are critically involved in a class of neurodegenerative diseases collectively called tauopathies and which includes Alzheimer's disease (AD) as its most common representative. In the course of the disease, tau changes its phosphorylation state and becomes hyperphosphorylated, gets truncated by proteolytic cleavage, is subject to O-glycosylation, sumoylation, ubiquitinylation, acetylation and some other modifications. This poses the important question, which of these posttranslational modifications are naturally occurring in the yeast model or can be reconstituted by heterologous gene expression. Here, we present an overview on common modifications as they occur in tau during AD, summarize their potential relevance with respect to disease mechanisms and refer to the native yeast enzyme orthologs capable to perform these modifications. We will also discuss potential approaches to humanize yeast in order to create modification patterns resembling the situation in mammalian cells, which could enhance the value of Saccharomyces cerevisiae and Kluyveromyces lactis as disease models.

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“…Additionally, excess extracellular glutamate leads to cellular influx of Ca2+. Recent studies reveal that Ca2+ stimulates the oligomeriztion of Aβ [162]. Therefore, it is plausible that the protracted influx of Ca2+ via the activation of NMDA receptors can promote the generation of toxic Aβ oligomers, working as a sort of positive feedback loop [163].…”

Section: Psycho-behavioural Anomalies As Diagnostic Marker For Neurolmentioning

confidence: 99%

Neurochemicals, Behaviours and Psychiatric Perspectives of Neurological Diseases

Choudhury¹,

Sahu²,

Ramanujam³

et al. 2018

Neuropsychiatry

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Structural changes in different regions of the brain have become clinically relevant and regarded as the signature phenomenon for neurological diseases. Morphological changes in brain are also associated with neuronal and neurochemical alterations. Studies have showed that minute changes in neurochemical levels may have marked impact on the psychobehaviour of the subject. Several neurological disease profiles have been reported with such specific psychobehavioural expression. However, application of behavioural abnormalities as possible disease progress markers has not been considered and emphasised much. Reports suggested that-the subjects, who have already entered into the terminal stage of the disease, used to show cardinal behavioural signs for a specific disease profile. However, psychological expressions are comparatively early expressive. As most of the neurodegenerative disorders are unidirectional and progressive by nature, therapeutic intervention at the right time is essential for attaining the desired outcome. Moreover, early diagnosis can aid in managing the disease progression also. Psychobehavioural analysis could meet the expected outcome of disease diagnosis if implemented properly and timely. In the present review, we have amalgamated the reported behavioural anomalies with the supportive background from neurochemical basis. Further, we have concluded that behaviour centric studies could be a potential diagnostic tool for the early diagnosis of major neurological diseases such as Alzheimer disease, Parkinson's disease, Amyotrophic lateral sclerosis (ALS), Bipolar disorder, Schizophrenia, Impulse control disorder (ICD) and Obsessive-compulsive disorder (OCD).

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Alzheimer's disease, β‐amyloid, glutamate, NMDA receptors and memantine – searching for the connections

Cited by 431 publications

References 257 publications

Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

Neurochemicals, Behaviours and Psychiatric Perspectives of Neurological Diseases

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