Glutamate system, amyloid ß peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology

Abstract

Alzheimer disease is the most prevalent form of dementia globally and is characterized premortem by a gradual memory loss and deterioration of higher cognitive functions and postmortem by neuritic plaques containing amyloid ß peptide and neurofibrillary tangles containing phospho-tau protein. Glutamate is the most abundant neurotransmitter in the brain and is essential to memory formation through processes such as long-term potentiation and so might be pivotal to Alzheimer disease progression. This review discusses how the glutamatergic system is impaired in Alzheimer disease and how interactions of amyloid ß and glutamate influence synaptic function, tau phosphorylation and neurodegeneration. Interestingly, glutamate not only influences amyloid ß production, but also amyloid ß can alter the levels of glutamate at the synapse, indicating that small changes in the concentrations of both molecules could influence Alzheimer disease progression. Finally, we describe how the glutamate receptor antagonist, memantine, has been used in the treatment of individuals with Alzheimer disease and discuss its effectiveness.

Fig. 1

The glutamate cycle. Glutamate is the most abundant neurotransmitter in the brain, and the levels of the amino acid are maintained in vesicles in the presynaptic neurons by 2 glutamate transporters, (1) VGLUT1 and 2. When the synapse is activated, glutamate is released into the synaptic cleft and activates 2 families of glutamate receptors, (2) ionotropic (iGluRs; N-methyl-d-aspartate [NMDA], α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and kainate) and metabotropic (mGluRs) receptors. N-methyl-d-aspartate receptors only become fully active after synchronised AMPA receptor activation and depolarization of the postsynaptic membrane. Glutamate receptor activation stimulates further downstream cellular pathways. (3) Glutamate is removed from the synaptic cleft by another group of glutamate transporters, which are mostly expressed in astrocytes, GLT-1 and GLAST in mice or EAAT1 and 2 in humans. Within astrocytes, (4) glutamate is converted to glutamine by glutamine synthetase and (5) returned to the presynaptic terminals where glutaminase converts glutamine back to glutamate. Many aspects of the glutamate cycle are affected in Alzheimer disease, implicating glutamate in disease progression. Amyloid β–related peptides have been shown to (A) increase glutamate release, (B) inhibit clearance of glutamate by astrocytes and (C) affect glutamate receptor activity.

Fig. 2

Effects of glutamate receptor activation on APP processing. The APP is cleaved via (A) nonamyloidogenic and (B) amyloidogenic pathways. (A) The nonamyloidogenic pathway precludes amyloid β production due to (1) α-secretase cleavage, by ADAM10 or ADAM17, of APP within the amyloid β domain, which (2) results in production of soluble APPα and α-CTF. (3) Short-term N-methyl-d-aspartate (NMDA) receptor activation increases the trafficking of ADAM10 to the cell membrane via interactions with SAP-97 and (4) metabotropic glutamate receptor activation of ADAM17 via PKC, thus increasing nonamyloidogenic APP processing. (B) The main β-secretase, BACE1, (5) initiates the production of amyloid β peptide, which occurs partly within the late-endosomes, by (6) cleaving APP into soluble APPβ and β-CTF. Prolonged NMDA receptor activation results in high Ca²⁺ levels and activation of CaMK-IV, which in turn enhances transcription of more amyloidogenic APP751 and APP770 isoforms. (7) The high Ca²⁺ levels also increase vesicle binding to the plasma membrane and subsequent transport of APP via endocytosis to late-endosomes, where it can be processed by BACE1. Thus, increased NMDA receptor activation enhances amyloidogenic processing of APP. The α- and β-CTFs generated from nonamyloidogenic and amyloidogenic pathways are further processed by the γ-secretase complex, leading to the formation of (8) AICD fragment, and the P3 or (9) amyloid β peptides, respectively. Activation of mGluRs 2 and 5 is also thought to increase generation of amyloid β peptide.