Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

Abstract

A direct relationship has been established between synaptic activity and amyloid-β secretion. Dysregulation of neuronal calcium homeostasis was shown to increase production of amyloid-β , contributing to the initiation of Alzheimer ' s disease. Among the different routes of Ca 2 + entry, N -methyld -aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, are especially involved in this process because of their ability to gate high levels of Ca 2 + infl ux. These receptors have been extensively studied for their crucial roles in synaptic plasticity that underlies learning and memory but also in neurotoxicity occurring during acute brain injuries and neurodegenerative diseases. For one decade, several studies provided evidence that NMDA receptor activation could have distinct consequences on neuronal fate, depending on their location. Synaptic NMDA receptor activation is neuroprotective, whereas extrasynaptic NMDA receptors trigger neuronal death and/or neurodegenerative processes. Recent data suggest that chronic activation of extrasynaptic NMDA receptors leads to a sustained neuronal amyloid-β release and could be involved in the pathogenesis of Alzheimer ' s disease. Thus, as for other neurological diseases, therapeutic targeting of extrasynaptic NMDA receptors could be a promising strategy. Following this concept, memantine, unlike other NMDA receptor antagonists was shown, to preferentially target the extrasynaptic NMDA receptor signaling pathways, while relatively sparing normal synaptic activity. This molecular mechanism could therefore explain why memantine is, to date, the only clinically approved NMDA receptor antagonist for the treatment of dementia.

Insulin potentiates the therapeutic effect of memantine against central STZ-induced spatial learning and memory deficit

“…This modulatory effect of memantine on STZ-induced learning deficit might be referred to STZ-induced glutamate excitotoxicity. STZ is shown to induce the release of calcium ions from intracellular sources which in turn stimulates the release of glutamate [18] and NMDA receptors over-activation leading to mitochondrial dysfunction and neuronal apoptosis that is similar to AD [19,20]. The results of this study confirm that memantine might help combating sAD like symptoms.…”

The Human Synaptic Vesicle Protein, SV2A, Functions as a Galactose Transporter in Saccharomyces cerevisiae

“…Abnormally enhanced glutamatergic neurotransmission is involved in the pathophysiology of epilepsy (24) and several neurodegenerative disorders, such as Parkinson disease, amyotrophic lateral sclerosis, Huntington disease, and Alzheimer disease (25,26). SV2A gained particular attention when it was identified as the binding site for the antiepileptic drug, levetiracetam (7).…”

Neuronal receptors as targets for the action of amyloid-beta protein (Aβ) in the brain

“…7). The two most common primary isoforms generated are Aβ 40 and Aβ 42 : the shorter form is typically produced by cleavage that occurs in the endoplasmic reticulum, whereas the longer form is produced by cleavage in the trans-Golgi network. The Aβ 40 form is the more predominant isoform produced by neurons and other cells, and accounts for over 70% of the total Aβ produced (Refs 24, 25), whereas Aβ 42 , which accounts for only 10-20% of total Aβ, is the major protein component of the Aβ neuritic plaques (Refs 24, 25).…”

“…27). Increases in either total Aβ levels or the relative concentrations of Aβ 40 and Aβ 42 , where the former is more concentrated in cerebrovascular plaques and the latter in neuritic plaques, have been suggested in the pathogenesis of both familial and sporadic AD, thus making it an important biomarker for this disease (Ref. 26).…”