Rodent Aβ(1–42) exhibits oxidative stress properties similar to those of human Aβ(1–42): Implications for proposed mechanisms of toxicity

Abstract

Alzheimer's disease is a neurodegenerative disorder associated with aging and cognitive decline. Amyloid beta peptide (1-42) [Aβ(1-42)] is a primary constituent of senile plaques-a hallmark of Alzheimer's disease-and has been implicated in the pathogenesis of the disease. Previous studies have shown that methionine residue 35 of Aβ(1-42) may play a critical role in Aβ(1-42)-mediated oxidative stress and neurotoxicity. Several additional mechanisms of neurotoxicity have been proposed, including the role of Cu(II) binding and reduction to produce hydrogen peroxide and the role of peptide aggregation. It has been reported that rodent Aβ is less likely to form larger β-sheet structures, and consequently, large aggregates. As a consequence of the lack of deposition of the peptide in rodent brain, rodent Aβ has been proposed to be non-toxic. Additionally, the sequence of the rodent variety of Aβ(1-42) contains three amino acid substitutions compared to the human sequence. These substitutions include the shift of arginine 5, trysosine 10, and histidine 13 to glycine, phenylalanine, and arginine, respectively. This shift in sequence within the Cu(II) binding region of the peptide results in a decrease in the ability of the rodent Aβ peptide to reduce Cu(II) to Cu(I) compared to the human Aβ peptide. As a result of the effect of the amino acid variations on the ability of the rodent peptide to reduce Cu(II) to Cu(I) compared to the human peptide, the rodent Aβ has been proposed to lack oxidative stress properties. In this study, the oxidative stress and neurotoxic properties of rodent Aβ(1-42) [Aβ(1-42)Rat] were evaluated and compared to those of human Aβ(1-42). Both human Aβ(1-42) and Aβ(1-42)Rat were found to have a significant effect on neuronal DNA fragmentation, loss of neuritic networks, and cell viability. Aβ(1-42) Rat was found to cause a significant increase in both protein oxidation and lipid peroxidation, similar to Aβ(1-42), both of which were inhibited by the lipid-soluble, chain breaking antioxidant vitamin E, suggesting that reactive oxygen species play a role in the Aβ-mediated toxicity. Taken together, these results suggest that Cu(II) reduction may not play a critical role in Aβ(1-42)Rat-induced oxidative stress, and that the oxidative stress exhibited by this peptide may be a consequence of the presence of methionine 35, similar to the findings associated with the native human Aβ(1-42) peptide.

Oxidative Stress and Neurotoxicity

“…At the same time, however, other studies have found evidence for a ROS detoxication role of A (100). Thus, despite the plethora of studies, more work will be needed if the field is going to reach a consensus on the role of A as being neurotoxic or neuroprotective (179), how either activity is modulated by metal complexation (180), and how dynamics of A aggregation alter neurotoxic vs neuroprotective properties as a function of time course of the disease. It must be appreciated that Amediated ROS generation could be unique to in vitro cellular systems, since there is no evidence that A causes oxidative stress in vivo (17).…”

Amphetamine effects on brain protein structure and oxidative stress as revealed by FTIR microspectroscopy

“…[44][45][46][47] Moreover, in the cascade of pathological events in AD, and possibly in ageing, the oxidative stress could be an important factor in the stimulation of the amyloidogenic pathway of the APP (amyloid precursor protein) and in the formation/accumulation of b-amyloid peptides. [48][49][50][51] If this theory is correct, other neurotoxicants increasing the formation of free radicals …”

“…Additionally, the sequence of the amyloid varieties in many mammals, such in rodents, contains aminoacid substitutions compared to the human sequence and are less likely to form larger b-structures although they produces a similar oxidative stress. 50 It should be noted that demonstration of amyloid peptides in brain of young animals has not been published up to day. Moreover, very different results have been observed using distinct antibodies against different amino acid sequences of amyloid peptides in aged animals when amyloid deposits have been studied.…”

Primate aging in the mammalian scheme: the puzzle of extreme variation in brain aging

“…With remarkably few exceptions (lab rodents), the Aβ sequence is identical in other vertebrates, including zebra fish (Coulson et al 2000). The absence of diffuse Aβ plaques in old lab rodents may be attributed to three amino acid differences that slow aggregation (Boyd-Kimball et al 2004). Besides its role in neurotoxicity (Klein et al 2001;Hardy 2009), the Aβ peptide also has strong anti-microbial activity (Soscia et al 2010), suggesting a basis for its evolutionary stability.…”

“…Whereas all primates examined share the same β-amyloid (Aβ1-42) amino acid sequence with humans, the Aβ peptide of lab rodents diverges from primates in three amino acids that reduce its spontaneous aggregation (Boyd-Kimball et al 2004). The absence of brain Aβ deposits in aging rodents gives an important comparative control in aging mechanisms because Aβ is pro-inflammatory and can activate astrocytes and microglia.…”