The synergy of β amyloid 1-42 and oxidative stress in the development of Alzheimer’s disease-like neurodegeneration of hippocampal cells

Abstract

Alzheimer’s disease (AD) is a type of dementia that affects memory, thinking and behavior. Symptoms eventually become severe enough to interfere with daily tasks. Understanding the etiology and pathogenesis of AD is necessary for the development of strategies for AD prevention and/or treatment, and modeling of this pathology is an important step in achieving this goal. β-amyloid peptide (Aβ) injection is a widely used approach for modeling AD. Nevertheless, it has been reported that the model constructed by injection of Aβ in combination with a prooxidant cocktail (ferrous sulfate, Aβ, and buthionine sulfoximine (BSO) (FAB)) best reflects the natural development of this disease. The relationship between oxidative stress and Aβ deposition and their respective roles in Aβ-induced pathology in different animal models of AD have been thoroughly investigated. In the current paper, we compared the effects of Aβ 1-42 alone with that of Aβ-associated oxidative stress induced by the FAB cocktail on the neurodegeneration of hippocampal cells in vitro. We constructed a FAB-induced AD model using rat primary hippocampal cells and analyzed the contribution of each compound. The study mainly focused on the prooxidant aspects of AD pathogenesis. Moreover, cellular bioenergetics was assessed and routine metabolic tests were performed to determine the usefulness of this model. The data clearly show that aggregated Aβ1-42 alone is significantly less toxic to hippocampal cells. Aggregated Aβ damages neurons, and glial cells proliferate to remove Aβ from the hippocampus. External prooxidant agents (Fe2+) or inhibition of internal antioxidant defense by BSO has more toxic effects on hippocampal cells than aggregated Aβ alone. Moreover, hippocampal cells fight against Aβ-induced damage more effectively than against oxidative damage. However, the combination of Aβ with external oxidative damage and inhibition of internal antioxidant defense is even more toxic, impairs cellular defense systems, and may mimic the late phase of AD-associated cell damage. Our findings strongly indicate a critical role for the combination of Aβ and oxidative stress in the development of neurodegeneration in vitro.

The contribution of initial concussive forces and resulting acrolein surge to β-amyloid accumulation and functional alterations in neuronal networks using a TBI-on-a-chip model

“…However, the majority of these increases are confined to neuronal cell bodies, which are well colocalized with elevated acrolein levels. This observation is in good agreement with multiple prior studies that have already linked increases of oxidative stress with elevated levels of Aβ42, 33,127,128 and further supports the causative role of acrolein in elevating Aβ42 aggregation (Fig. 9).…”

“…Further, we decided to investigate impact-induced changes in levels of the Aβ42 protein, a target whose increased accumulation in the brain is widely recognized as an early event in AD pathogenesis, [27][28][29] and is thought to be closely related to changes in both oxidative stress and inflammation. [30][31][32][33] As such, we aimed to deconstruct these complicated relationships, by simultaneously investigating all of the aforementioned experimental conditions while concurrently isolating primary and secondary injuries that link mechanical force to protein aggregation at the cellular and molecular level, with unprecedented spatial and temporal resolution.…”

Roles of Oxidative Stress in Synaptic Dysfunction and Neuronal Cell Death in Alzheimer’s Disease

“…In primary cultures of human fetal neurons, Aβ 1–42 treatments (0.5–50 μmol/L) caused a time-independent and concentration-dependent reduction of electrophysiological responses (whole-cell outward currents) and significant neurotoxicity, particularly inducing caspase-dependent and caspase-independent apoptotic cell death [ 15 ]. Primary hippocampal cells from a rat AD model showed oxidative stress responses to Aβ 1–42 and Aβ 1–42 combined with Fe(II)+buthionine sulfoximine, indicating that Aβ formulations triggered prooxidant aspects of AD pathogenesis [ 16 ]. The neurotoxic effects of Aβ are enhanced by the prooxidant compounds Fe(II)+buthionine sulfoximine, indicating a synergistic effect to damage hippocampal neurons and glia cells.…”

Alzheimer's Disease: Status of Low‐Dimensional Nanotherapeutic Materials

“…[82] Moreover, A𝛽 themselves can also accelerate ROS generation, oxidative stress, and cell apoptosis. [79,83] Aggregation of p-Tau monomers will form oligomers, which may affect mitochondrion inducing oxidative stress in cells. [84] p-Tau can also disrupt axonal transport, leading to abnormal mitochondrial distribution.…”