Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer's Disease: Understanding the Therapeutics Strategies

Abstract

Synapses are formed by interneuronal connections that permit a neuronal cell to pass an electrical or chemical signal to another cell. This passage usually gets damaged or lost in most of the neurodegenerative diseases. It is widely believed that the synaptic dysfunction and synapse loss contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although pathological hallmarks of AD are senile plaques, neurofibrillary tangles, and neuronal degeneration which are associated with increased oxidative stress, synaptic loss is an early event in the pathogenesis of AD. The involvement of major kinases such as mitogen-activated protein kinase (MAPK), extracellular receptor kinase (ERK), calmodulin-dependent protein kinase (CaMKII), glycogen synthase-3β (GSK-3β), cAMP response element-binding protein (CREB), and calcineurin is dynamically associated with oxidative stress-mediated abnormal hyperphosphorylation of tau and suggests that alteration of these kinases could exclusively be involved in the pathogenesis of AD. N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation and beta amyloid (Aβ) toxicity alter the synapse function, which is also associated with protein phosphatase (PP) inhibition and tau hyperphosphorylation (two main events of AD). However, the involvement of oxidative stress in synapse dysfunction is poorly understood. Oxidative stress and free radical generation in the brain along with excitotoxicity leads to neuronal cell death. It is inferred from several studies that excitotoxicity, free radical generation, and altered synaptic function encouraged by oxidative stress are associated with AD pathology. NMDARs maintain neuronal excitability, Ca(2+) influx, and memory formation through mechanisms of synaptic plasticity. Recently, we have reported the mechanism of the synapse redox stress associated with NMDARs altered expression. We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis.

Keywords: Alzheimer’s disease; Kinases; NMDA receptor; Oxidative stress; Synaptic function; Tau protein.

Fig. 1

Comparative changes in healthy and diseased neuron implicated in AD pathogenesis. The abnormal function of Aβ activates several stress-related kinases that results in damaged nucleus and mitochondria in diseased neurons in AD pathogenesis

Fig. 2

Structure of synapse: Synapse is a specialized communication junction between two cells comprised of two major units: a presynaptic cell (usually a neuron) that sends out a signal and a postsynaptic cell that receives the signal. Neurotransmitter molecules diffuse across the synaptic cleft and bind to their specific receptors on the postsynaptic cell. This recreates the action potential in the postsynaptic cell. This channel usually gets damaged or lost in neurodegenerative diseases

Fig. 3

Synapse dysfunction: as a consequence of MAPK and mitochondrial oxidative stress-mediated tau hyperphosphorylation. β-Amyloid activates several stress-related kinases that causes oxidative stress. The phosphorylation/activation of ERK1/2 and MEK1/2 via MAPK results in apoptosis. Consequently, abnormal hyperphosphorylation of tau leads to synapse dysfunction. Aβ also results in mitochondrial dysfunction by affecting the prosurvival protein Bcl-2. The mitochondrial-mediated caspase pathway gets triggered by the Bcl-2 family of proteins, then cytochrome c release, and finally, apoptosis. This ultimately leads to synapse dysfunction

Fig. 4

Molecular mechanism of tau phosphorylation mediated synaptic dysfunction: High level of Aβ production is directly correlated with critical event for synaptic dysfunction, i.e., formation of tangles. Excitotoxic cell death (ECD) is an event due to increased intracellular Ca²⁺ by overstimulation of NMDA receptor. Overstimulation of NMDAR leads to upregulation of detrimental signaling pathways, disrupting Ca²⁺ homeostasis and oxidative/nitrosative stress ultimately toward apoptosis. The mitochondrial oxidative stress and the release of cytochrome c, activation of caspase-9, and subsequently of caspase-3 cause neuronal damage. Mitochondria-mediated oxidative stress influences tau function resulting in the hyperphosphorylation of tau which governs the major synaptic dysfunction by forming tangles

Fig. 5

Beta amyloid-mediated synapse loss: Deposition of amyloid plaques (Aβ) is characterized in Alzheimer’s disease (AD) which affects NMDAR resulting in dendritic damage caused due to mitochondrial oxidative stress as a consequence of excitotoxicity. Aβ also trigger NMDA mediated Ca²⁺ influx which results in dendritic spine toxicity mediated by CREB and hyperphosphorylation of Tau. Ca²⁺ influx can also lead to mitochondrial oxidative stress along with caspase-3-mediated apoptosis and tau hyperphosphorylation and ultimately leads to synapse loss