Differential regulation of the high‐affinity choline transporter by wild‐type and Swedish mutant amyloid precursor protein

Cuddy, Leah K.; Seah, Claudia; Pasternak, Stephen

doi:10.1111/jnc.13167

Cited by 12 publications

(10 citation statements)

References 43 publications

(91 reference statements)

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“…The purpose of the present study was to investigate the effect of Aβ peptides released into conditioned medium (CM) from neural cells expressing Swedish mutant APP (CM-APP Swe ) on CHT trafficking and activity, and to determine whether this is altered by anti-Aβ antibodies. We found recently that expression of APP Swe in neural cells decreases CHT function when compared to wild-type APP with this related to increased APP Swe processing (Cuddy et al, 2015 ). We now make the novel observation that treatment of neural cells with CM that contains Aβ peptides from cells expressing APP Swe decreases CHT co-localization with the early endosome marker EEA1 and lysosome marker LAMP-1, suggesting that Aβ-mediated inhibition of CHT function is related to a loss of CHT proteins from endocytic recycling compartments.…”

Section: Introductionmentioning

confidence: 94%

Amino-Terminal β-Amyloid Antibody Blocks β-Amyloid-Mediated Inhibition of the High-Affinity Choline Transporter CHT

Cuddy

Seah

Pasternak

2017

Front. Mol. Neurosci.

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Alzheimer’s disease (AD) is a common age-related neurodegenerative disorder that is characterized by progressive cognitive decline. The deficits in cognition and attentional processing that are observed clinically in AD are linked to impaired function of cholinergic neurons that release the neurotransmitter acetylcholine (ACh). The high-affinity choline transporter (CHT) is present at the presynaptic cholinergic nerve terminal and is responsible for the reuptake of choline produced by hydrolysis of ACh following its release. Disruption of CHT function leads to decreased choline uptake and ACh synthesis, leading to impaired cholinergic neurotransmission. We report here that cell-derived β-amyloid peptides (Aβ) decrease choline uptake activity and cell surface CHT protein levels in SH-SY5Y neural cells. Moreover, we make the novel observation that the amount of CHT protein localizing to early endosomes and lysosomes is decreased significantly in cells that have been treated with cell culture medium that contains Aβ peptides released from neural cells. The Aβ-mediated loss of CHT proteins from lysosomes is prevented by blocking lysosomal degradation of CHT with the lysosome inhibitor bafilomycin A1 (BafA1). BafA1 also attenuated the Aβ-mediated decrease in CHT cell surface expression. Interestingly, however, lysosome inhibition did not block the effect of Aβ on CHT activity. Importantly, neutralizing Aβ using an anti-Aβ antibody directed at the N-terminal amino acids 1–16 of Aβ, but not by an antibody directed at the mid-region amino acids 22–35 of Aβ, attenuates the effect of Aβ on CHT activity and trafficking. This indicates that a specific N-terminal Aβ epitope, or specific conformation of soluble Aβ, may impair CHT activity. Therefore, Aβ immunotherapy may be a more effective therapeutic strategy for slowing the progression of cognitive decline in AD than therapies designed to promote CHT cell surface levels.

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Section: Introductionmentioning

confidence: 94%

Amino-Terminal β-Amyloid Antibody Blocks β-Amyloid-Mediated Inhibition of the High-Affinity Choline Transporter CHT

Cuddy

Seah

Pasternak

2017

Front. Mol. Neurosci.

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“…) and even more complexity is revealed by new findings that APP interacts with choline transport and its trafficking is sensitive to APP genetic mutants (Cuddy et al . ).…”

Section: Cholinergic Transmission Signalling and Pathobiologymentioning

confidence: 97%

“…Other possible targets here include a4-nicotinic AChRs which play a role in remodelling of spine architecture underpinning the cholinergic tuning of brain function and in associated hippocampal synaptic development and plasticity (Nordman et al 2014;Oda et al 2014). Even more surprisingly choline proves to be a potent direct regulator via both muscarinic and nicotinic AChRs of patterned activity within hippocampal networks (Fischer et al 2014) and even more complexity is revealed by new findings that APP interacts with choline transport and its trafficking is sensitive to APP genetic mutants (Cuddy et al 2015).…”

Section: Cholinergic Transmission Signalling and Pathobiologymentioning

confidence: 99%

Synaptic signalling and its interface with neuropathologies: snapshots from the past, present and future

Beart

2016

Journal of Neurochemistry

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This 'Past to Future' Review as part of the 60th anniversary year of the Journal of Neurochemistry focuses on synaptic transmission and associated signalling, and seeks to identify seminal progress in neurochemistry over the last 10 years which has advanced our understanding of neuronal communication in brain. The approach adopted analyses neurotransmitters on a case by case basis (i.e. amino acids, monoamines, acetylcholine, neuropeptides, ATP/purines and gasotransmitters) to highlight novel findings that have changed the way we view each type of transmitter, to explore commonalities and interactions, and to note how new insights have changed the way we view the biology of degenerative, psychiatric and behavioural conditions. Across all transmitter systems there was remarkable growth in the identification of targets likely to provide therapeutic benefit and which undoubtedly was driven by the elucidation of circuit function and new vistas of synaptic signalling. There has been an increasing trend to relate signalling to disease, notably for Alzheimer's and Parkinson's disease and related conditions, and which has occurred for each transmitter family. Forebrain circuitry and tonic excitatory control have been the centre of great attention yielding novel findings that will impact upon cognitive, emotional and addictive behaviours. Other impressive insights focus on gasotransmitters integrating activity as volume transmitters. Exciting developments in how serotonin, cholinergic, l-glutamate, galanin and adenosine receptors and their associated signalling can be beneficially targeted should underpin the development of new therapies. Clearly integrated, multifaceted neurochemistry has changed the way we view synaptic signalling and its relevance to pathobiology. Highlighted are important advances in synaptic signalling over the last decade in the Journal of Neurochemistry. Across all transmitter systems elucidation of circuit function, and notably molecular insights, have underpinned remarkable growth in the identification of targets likely to provide therapeutic benefit in neuropathologies. Another commonality was wide interest in forebrain circuitry and its tonic excitatory control. Increasingly observations relate to signalling in disease and behavioural conditions. This article is part of the 60th Anniversary special issue.

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“…CHT1 is specifically localized on presynaptic cholinergic nerve terminals and is directly involved in the high-affinity choline uptake (HACU) transport, a key regulatory step in the synthesis of ACh. CHT1 transporters actively transport choline from the synapsis back to the presynaptic terminals, where it is used for the de novo synthesis of ACh [18,19,20,21,22,23,24]. In contrast to AChE, however, the 3D structure of the transmembrane CHT1 is not known in details yet.…”

Section: Introductionmentioning

confidence: 99%

“…Recent research indicates that CHT1 is localized predominantly within lipid rafts in neuronal membranes, where it colocalizes with the amyloid precursor protein (APP). It appears that APP regulates the cell surface levels of CHT1 via increased endocytosis and thus directly attenuates HACU activity [23,24]. The disruption of lipid rafts, e.g., by removing membrane cholesterol by methyl-β-cyclodextrine, thus enables in vitro investigations of CHT1 interactions under pathological conditions.…”

Section: Introductionmentioning

confidence: 99%

Inhibitors of Acetylcholinesterase Derived from 7-Methoxytacrine and Their Effects on the Choline Transporter CHT1

Krištofiková¹,

Říčný²,

Soukup³

et al. 2016

Dement Geriatr Cogn Disord

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Background: Reversible acetylcholinesterase inhibitors are used in Alzheimer disease therapy. However, tacrine and its derivatives have severe side effects. Derivatives of the tacrine analogue 7-methoxytacrine (MEOTA) are less toxic. Methods: We evaluated new derivatives of 7-MEOTA (2 homodimers linked by 2 C₄-C₅ chains and 5 N-alkylated C₄-C₈ side chain derivatives) in vitro, using the rat hippocampal choline transporter CHT1. Results: Some derivatives were effective inhibitors of rat acetylcholinesterase and comparable with 7-MEOTA. All derivatives were able to inhibit CHT1, probably via quaternary ammonium, and this interaction could be involved in the enhancement of their detrimental side effects and/or in the attenuation of their promising effects. Under conditions of disrupted lipid rafts, the unfavorable effects of some derivatives were weakened. Only tacrine was probably able to stereospecifically interact with the naturally occurring amyloid-β isoform and to simultaneously stimulate CHT1. Some derivatives, when coincubated with amyloid β, did not influence CHT1. All derivatives also increased the fluidity of the cortical membranes. Conclusion: The N-alkylated derivative of 7-MEOTA bearing from C₄ side chains appears to be the most promising compound and should be evaluated in future in vivo research.

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Differential regulation of the high‐affinity choline transporter by wild‐type and Swedish mutant amyloid precursor protein

Cited by 12 publications

References 43 publications

Amino-Terminal β-Amyloid Antibody Blocks β-Amyloid-Mediated Inhibition of the High-Affinity Choline Transporter CHT

Amino-Terminal β-Amyloid Antibody Blocks β-Amyloid-Mediated Inhibition of the High-Affinity Choline Transporter CHT

Synaptic signalling and its interface with neuropathologies: snapshots from the past, present and future

Inhibitors of Acetylcholinesterase Derived from 7-Methoxytacrine and Their Effects on the Choline Transporter CHT1

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