Cortical Pyramidal Neurone Loss May Cause Glutamatergic Hypoactivity and Cognitive Impairment in Alzheimer's Disease: Investigative and Therapeutic Perspectives

Francis, Paul T.; Sims, Neil R.; Procter, Andrew W.; Bowen, David M.

doi:10.1111/j.1471-4159.1993.tb13381.x

Cited by 216 publications

(121 citation statements)

References 148 publications

Supporting

Mentioning

109

Contrasting

Unclassified

Order By: Relevance

“…The binding of copper to Aβ is likely to be a factor in AD because copper, too, is enriched in amyloid plaque [82]. Copper and Aβ are both released into the glutamatergic synaptic cleft, where hypoactiivty of the glutamate receptor, NMDA [181], is thought to contribute to cognitive decline in AD [182]. The co-release of copper and Aβ might make them available for pathological interactions.…”

Section: Coppermentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

View full text Add to dashboard Cite

No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

show abstract

Section: Coppermentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

View full text Add to dashboard Cite

show abstract

“…Again it has been shown that glutamate transmission, which is defective in AD, can be pharmacologically modulated using antagonists of 5-HT 1A receptors in cerebral cortex [15,53] and in the hippocampus [11], suggesting that also AD patients may benefit from a treatment with serotonergic drugs.…”

Section: Role Of 5-ht-mediated Modulation In Learning and Memorymentioning

confidence: 99%

Serotonin as a Modulator of Glutamate- and GABA-Mediated Neurotransmission: Implications in Physiological Functions and in Pathology

Ciranna

2006

268

170

View full text Add to dashboard Cite

Abstract:The neurotransmitter serotonin (5-HT), widely distributed in the central nervous system (CNS), is involved in a large variety of physiological functions. In several brain regions 5-HT is diffusely released by volume transmission and behaves as a neuromodulator rather than as a "classical" neurotransmitter. In some cases 5-HT is co-localized in the same nerve terminal with other neurotransmitters and reciprocal interactions take place. This review will focus on the modulatory action of 5-HT on the effects of glutamate and -amino-butyric acid (GABA), which are the principal neurotransmitters mediating respectively excitatory and inhibitory signals in the CNS. Examples of interaction at preand/or post-synaptic levels will be illustrated, as well as the receptors involved and their mechanisms of action. Finally, the physiological meaning of neuromodulatory effects of 5-HT will be briefly discussed with respect to pathologies deriving from malfunctioning of serotonin system.

show abstract

“…Furthermore, other studies have provided evidence that overexpression of htau in transgenic mice caused extensive organelle swelling and cytoplasmic vacuolization more suggestive of necrosis and likely of glutamatemediated excitotoxicity (9). In this context, it is known that N-methyl-D-aspartate receptor (NMDAR)-expressing neurons are vulnerable to AD loss, supporting the hypothesis of excitotoxic NMDAR activity-mediated death in AD (15)(16)(17).…”

mentioning

confidence: 99%

NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation

Amadoro

Ciotti

Costanzi

et al. 2006

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

222

156

View full text Add to dashboard Cite

The altered function and͞or structure of tau protein is postulated to cause cell death in tauopathies and Alzheimer's disease. However, the mechanisms by which tau induces neuronal death remain unclear. Here we show that overexpression of human tau and of some of its N-terminal fragments in primary neuronal cultures leads to an N-methyl-D-aspartate receptor (NMDAR)-mediated and caspase-independent cell death. Death signaling likely originates from stimulation of extrasynaptic NR2B-subunit-containing NMDARs because it is accompanied by dephosphorylation of cAMP-response-element-binding protein (CREB) and it is inhibited by ifenprodil. Interestingly, activation of NMDAR leads to a crucial, sustained, and delayed phosphorylation of extracellular-regulated kinases 1 and 2, whose inhibition largely prevents tau-induced neuronal death. Moreover, NMDAR involvement causes the fatal activation of calpain, which, in turn, degrades tau protein into a 17-kDa peptide and possibly other highly toxic N-terminal peptides. Some of these peptides are hypothesized, on the basis of our in vitro experiments, to initiate a negative loop, ultimately leading to cell death. Thus, inhibition of calpain largely prevents tau degradation and cell death. Our findings unravel a cellular mechanism linking tau toxicity to NMDAR activation and might be relevant to Alzheimer's disease and tauopathies where NMDARmediated toxicity is postulated to play a pivotal role. extracellular-regulated kinase ͉ mitogen-activated protein kinase ͉ neurodegenerative diseases ͉ glutamate receptors ͉ Alzheimer's disease

show abstract

Cortical Pyramidal Neurone Loss May Cause Glutamatergic Hypoactivity and Cognitive Impairment in Alzheimer's Disease: Investigative and Therapeutic Perspectives

Cited by 216 publications

References 148 publications

Biometals and Their Therapeutic Implications in Alzheimer's Disease

Biometals and Their Therapeutic Implications in Alzheimer's Disease

Serotonin as a Modulator of Glutamate- and GABA-Mediated Neurotransmission: Implications in Physiological Functions and in Pathology

NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation

Contact Info

Product

Resources

About