The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is the most common form of dementia in individuals over 65 years of age and is characterized by accumulation of beta-amyloid (Aβ) and tau. Both Aβ and tau alter synaptic plasticity, leading to synapse loss, neural network dysfunction, and eventually neuron loss. However, the exact mechanism by which these proteins cause neurodegeneration is still not clear. A growing body of evidence suggests perturbations in the glutamatergic tripartite synapse, comprised of a presynaptic terminal, a postsynaptic spine, and an astrocytic process, may underlie the pathogenic mechanisms of AD. Glutamate is the primary excitatory neurotransmitter in the brain and plays an important role in learning and memory, but alterations in glutamatergic signaling can lead to excitotoxicity. This review discusses the ways in which both beta-amyloid (Aβ) and tau act alone and in concert to perturb synaptic functioning of the tripartite synapse, including alterations in glutamate release, astrocytic uptake, and receptor signaling. Particular emphasis is given to the role of N-methyl-D-aspartate (NMDA) as a possible convergence point for Aβ and tau toxicity.

Distribution of LIM domain kinase 1 in the olfactory bulb, cerebral cortex, hippocampus, and cerebellum of the App/PS+/- mice

“…Therefore, we studied the relationship between LIMK1 and AD in the mouse brain. AD is the most common form of dementia in patients, and it is characterized by the accumulation of Aβ, which leads to the impairment of learning and memory and thus cognitive deficits (Rudy et al, 2015).…”

“…This might explain neurological INTRODUCTION β-amyloid (Aβ), a product of β-amyloid precursor protein (APP), is aggregated into oligomers, fibrils and plaques, which is a central phenomenon in the molecular pathogenesis of Alzheimer's disease (AD) (Vorobyeva et al, 2014;Rudy et al, 2015). AD is a progressive neurodegenerative disorder leading to memory loss and cognitive deficits (Piau et al, 2011;Rudy et al, 2015). Presenilin (PS) is part of the γ-secretase complex, and it is responsible for AD with an earlier age of onset.…”

Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders

“…GWASs, linkage studies, and candidate gene studies in BD or MDD were included that investigated chromosomal regions or SNPs of genes involved in pathways/mediators related to the so-called tripartite glutamate synapse, comprising pre-and post-synaptic neurons and glial cells. The following specific terms were selected for inclusion from recently published non-systematic reviews (Duman, 2014;Machado-Vieira et al, 2009;Mathews et al, 2012;Rudy et al, 2015): 'Vesicular Glutamate Transport Proteins', 'SNARE Proteins', 'Voltage-Gated Sodium Channels', 'Receptors, Metabotropic Glutamate', 'Postsynaptic Density Proteins', 'Receptors, AMPA', 'Receptors, NMDA', 'Receptors, Kainic Acid', 'Glutamate Plasma Membrane Transport Proteins', and 'Glutamic Acid'. A literature search was performed on PubMed and Web of Science databases in March 2016 using the medical subject heading (MeSH) 'Mood Disorders' associated with the other aforementioned MeSH terms.…”

Neurochemicals, Behaviours and Psychiatric Perspectives of Neurological Diseases

“…The most common symptom of early stage AD is the difficulty in remembering recent events and newly learned information. The major pathological features of AD include progressive loss of cholinergic neurons in the basal forebrain, accumulation of extracellular senile plaques containing amyloid-β peptide (Aβ), and accumulation of intracellular neurofibrillary tangles (NFT), containing hyper phosphorylated tau (P-tau) [148]. Both Aβ plaques and tau NFTs are known to alter synaptic plasticity, leading to dysfunction of the neural network, synapse loss, and eventually neuron loss.…”

“…Changes in the prefrontal, cingulate cortices, and the hippocampus are observed since the early stages of the disease [17]. In addition to the degeneration of anatomical pathways17, genetic factors, environmental factors, mitochondrial dysfunction, immune dysfunction, vascular factors, infectious agents might also have a role in pathogenesis of AD [148]. However, inspite of our extensive understanding of AD, there is still no cure for this multifactorial disorder.…”