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, Ca2+ 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.

Autophagy in synaptic development, function, and pathology

“…2A), local protein clearance and turnover (Fig. 2B) Alzheimer's disease [AD] [58,59] and Parkinson's disease…”

Rubidium and potassium levels are altered in Alzheimer’s disease brain and blood but not in cerebrospinal fluid

“…Oxidative stress arising from neurotoxic β-amyloid (Aβ) accumulation and oligomerization causes a loss in membrane integrity in the synapse [2], which is heavily dependent on sufficient ATP production to regulate ion transport in and out of the cell [3]. Oligomeric Aβ species adversely affect cellular function through a range of hypothesized mechanisms, a number of which directly compromise both energy production and membrane potential [4, 5].…”

nNOS–CAPON interaction mediates amyloid‐β‐induced neurotoxicity, especially in the early stages

“…Therefore, blocking nNOS–CAPON interaction might induce fewer side effects than the direct intervention of NMDARs or nNOS. The ERK–CREB–BDNF pathway is important for maintaining the survival and function of neurons in Alzheimer's disease, and increased activation of this pathway might slow the development of Alzheimer's disease (Kamat et al., 2016). The beneficial effects of blocking nNOS–CAPON interaction come from the recovery of dendrites and the ERK–CREB–BDNF pathway, and thus, this approach is different from blocking NMDARs, such as with memantine, which decreases the influx of Ca 2+ and excitotoxicity (Ferreira‐Vieira, Guimaraes, Silva & Ribeiro, 2016).…”