Glutamatergic systems in Alzheimer's disease

Francis, Paul T.

doi:10.1002/gps.934

Cited by 209 publications

(142 citation statements)

References 63 publications

Supporting

Mentioning

130

Contrasting

Unclassified

Order By: Relevance

“…While excitotoxicity has been proposed as a mechanism of neuronal death and cognitive decline associated with AD [43], the concentration of A␤ 42 evoked glutamate release observed in this study is not in the neurotoxic range for an intact CNS abundant in glia under normal conditions [15]. Rather, the progressive accumulation of A␤ 42 during disease progression could lead to persistent activation of the ␣7nAChR and chronically elevate glutamate release that, over time, results in excitotoxicity.…”

Section: Discussionmentioning

confidence: 55%

“…A␤ 42 binds to the ␣7 nicotinic acetylcholine receptor (␣7nAChR) with picomolar affinity [10] and activation of this receptor is known to stimulate glutamate release [11]. Glutamate, the predominant excitatory neurotransmitter in the mammalian CNS, has a strong prevalence in neocortical and hippocampal pyramidal neurons and, therefore, plays a critical role in learning and memory [12]. Furthermore, picomolar concentrations of A␤ 42 can enhance synaptic plasticity and reference memory through activation of the ␣7nAChR [13].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Soluble Amyloid-β42 Stimulates Glutamate Release through Activation of the α7 Nicotinic Acetylcholine Receptor

Hascup

2016

JAD

View full text Add to dashboard Cite

Abstract. Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and hippocampal atrophy. Soluble amyloid-␤ (A␤) 42 and plaque accumulation is implicated as the neurotoxic species in this disorder; however, at physiological concentrations (pM-nM), A␤ 42 contributes to neurogenesis, long-term potentiation, and neuromodulation. Because A␤ 42 binds the ␣7 nicotinic acetylcholine receptors (␣7nAChRs) located presynaptically on glutamatergic terminals, involved with hippocampal dependent learning and memory, we examined the effects of the human, monomeric isoform of A␤ 42 on glutamate release in the dentate gyrus (DG), CA3, and CA1, of isoflurane anesthetized, 6-9 month old male C57BL/6J mice. We utilized an enzyme-based microelectrode array selective for L-glutamate measures with fast temporal (4 Hz), low spatial resolution (50 × 100 m) and minimal damage to the surrounding parenchyma (50-100 m). Local application of A␤ 42 (0.01, 0.1, 1.0, and 10.0 M; ∼150 nl; 1-2 Seconds) elicited robust, reproducible glutamate signals in all hippocampal subfields studied. Local application of 0.1 and 1.0 M A␤ 42 significantly increased the average maximal amplitude of glutamate release compared to saline in the DG and CA1. 10.0 M A␤ 42 significantly elevated glutamate release in the DG and CA3, but not in the CA1. Glutamate release was completely attenuated with coapplication of 10.0 M ␣-Bungarotoxin, the potent ␣7nAChR antagonist. Coapplication of 10.0 M tetrodotoxin, indicates A␤ 42-induced glutamate release originates from neuronal rather than glial sources. This study demonstrates that the human, monomeric A␤ 42 isoform evokes glutamate release through the ␣7nAChR and varies across hippocampal subfields.

show abstract

Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Soluble Amyloid-β42 Stimulates Glutamate Release through Activation of the α7 Nicotinic Acetylcholine Receptor

Hascup

2016

JAD

View full text Add to dashboard Cite

show abstract

“…Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamatergic neurons are located in areas that are targeted by the AD pathological cascade (62,63). Disruption in glutamatergic signalling has been reported in both animal models of AD and people with dementia (62,64).…”

Section: Relevance To Alzheimer's Diseasementioning

confidence: 99%

“…Disruption in glutamatergic signalling has been reported in both animal models of AD and people with dementia (62,64). Indeed a breakdown in glutamate homeostasis forms the basis of the 'glutamatergic' hypothesis in AD (65)(66)(67).…”

Section: Relevance To Alzheimer's Diseasementioning

confidence: 99%

Astrocytic transporters in Alzheimer's disease

Ugbode

Whalley

et al. 2017

Biochemical Journal

View full text Add to dashboard Cite

Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.

show abstract

“…It is known that Glu receptors (GluRs) are involved in AD, and it is thought that GluR-mediated toxicity plays an important role in cell loss associated with the disease (4,5,8,12,13). Most of the evidence comes from animal models and binding experiments in different regions of the human brain (14)(15)(16)(17)(18), but so far, no direct analyses of the function of the receptors have been made.…”

mentioning

confidence: 99%

Properties of glutamate receptors of Alzheimer's disease brain transplanted to frog oocytes

Bernareggi

Dueñas²,

Reyes-Ruiz³

et al. 2007

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

View full text Add to dashboard Cite

It is known that Alzheimer's disease (AD) is a synaptic disease that involves various neurotransmitter systems, particularly those where synaptic transmission is mediated by acetylcholine or glutamate (Glu). Nevertheless, very little is known about the properties of neurotransmitter receptors of the AD human brain. We have shown previously that cell membranes, carrying neurotransmitter receptors from the human postmortem brain, can be transplanted to frog oocytes, and their receptors will still be functional. Taking advantage of this fact, we have now studied the properties of Glu receptors (GluRs) from the cerebral cortices of AD and non-AD brains and found that oocytes injected with AD membranes acquired GluRs that have essentially the same functional properties as those of oocytes injected with membranes from non-AD brains. However, the amplitudes of the currents elicited by Glu were always smaller in the oocytes injected with membranes from AD brains. Western blot analyses of the same membrane preparations used for the electrophysiological studies showed that AD membranes contained significantly fewer GluR2/3 subunit proteins. Furthermore, the corresponding mRNAs were also diminished in the AD brain. Therefore, the smaller amplitude of membrane currents elicited by Glu in oocytes injected with membranes from an AD brain is a consequence of a reduced number of GluRs in cell membranes transplanted from the AD brain. Thus, using the comparatively simple method of microtransplantation of receptors, it is now possible to determine the properties of neurotransmitter receptors of normal and diseased human brains. That knowledge may help to decipher the etiology of the diseases and also to develop new treatments.neurotransmitter receptors ͉ postmortem brain ͉ Xenopus oocytes

show abstract

Glutamatergic systems in Alzheimer's disease

Cited by 209 publications

References 63 publications

Soluble Amyloid-β42 Stimulates Glutamate Release through Activation of the α7 Nicotinic Acetylcholine Receptor

Soluble Amyloid-β42 Stimulates Glutamate Release through Activation of the α7 Nicotinic Acetylcholine Receptor

Astrocytic transporters in Alzheimer's disease

Properties of glutamate receptors of Alzheimer's disease brain transplanted to frog oocytes

Contact Info

Product

Resources

About