Alterations on Na+,K+-ATPase and Acetylcholinesterase Activities Induced by Amyloid-β Peptide in Rat Brain and GM1 Ganglioside Neuroprotective Action

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder whose pathogenesis involves production and aggregation of amyloid-β peptide (Aβ). Aβ-induced toxicity is believed to involve alterations on as Na(+),K(+)-ATPase and acetylcholinesterase (AChE) activities, prior to neuronal death. Drugs able to prevent or to reverse these biochemical changes promote neuroprotection. GM1 is a ganglioside proposed to have neuroprotective roles in AD models, through mechanisms not yet fully understood. Therefore, this study aimed to investigate the effect of Aβ1-42 infusion and GM1 treatment on recognition memory and on Na(+),K(+)-ATPase and AChE activities, as well as, on antioxidant defense in the brain cortex and the hippocampus. For these purposes, Wistar rats received i.c.v. infusion of fibrilar Aβ1-42 (2 nmol) and/or GM1 (0.30 mg/kg). Behavioral and biochemical analyses were conducted 1 month after the infusion procedures. Our results showed that GM1 treatment prevented Aβ-induced cognitive deficit, corroborating its neuroprotective function. Aβ impaired Na(+),K(+)-ATPase and increase AChE activities in hippocampus and cortex, respectively. GM1, in turn, has partially prevented Aβ-induced alteration on Na(+),K(+)-ATPase, though with no impact on AChE activity. Aβ caused a decrease in antioxidant defense, specifically in hippocampus, an effect that was prevented by GM1 treatment. GM1, both in cortex and hippocampus, was able to increase antioxidant scavenge capacity. Our results suggest that Aβ-triggered cognitive deficit involves region-specific alterations on Na(+),K(+)-ATPase and AChE activities, and that GM1 neuroprotection involves modulation of Na(+),K(+)-ATPase, maybe by its antioxidant properties. Although extrapolation from animal findings is difficult, it is conceivable that GM1 could play an important role in AD treatment.

Neuroprotective Effects of Pomegranate Peel Extract after Chronic Infusion with Amyloid-β Peptide in Mice

“…This result was not expected, as many works have already shown that Aβ-treated animals normally present increases in AChE activity. However, in those works, the doses used were at least 32 times higher (0.159 nmol/μL to 2,0 nmol/ μL) than the dose used in the present work (0.005 nmol/μL) and the researchers made a single injection (or three single injections) of the Aβ (1–40 or 1–42), and not a chronic infusion [47,48,49,50,51]. In previous works, our research team observed neuron degeneration in the cortex and hippocampus and loss of memory in animals infused with 0.005 nmol/μL [18,19,29,52].…”

Acetylcholinesterase Protein Level Is Preserved in the Alzheimer's Brain

“…However, it is not clear whether the atypical histochemical behavior of AChE observed in AD is due to alterations in kinetic properties of these enzymes (Ciro et al, 2012), or due to interactions with other molecules within these lesions (Darvesh et al, 2010). In the context of the presence of AChE within plaques and NFT, it is important to note that both AD effectors, Aβ and abnormally hyperphosphorylated tau, can influence AChE levels in vitro (Sberna et al, 1997;Sáez-Valero et al, 2003;Hu et al, 2003;Melo et al, 2003) and in rodent models (Sberna et al, 1998;Sáez-Valero et al, 2002;Silveyra et al, 2012b;Kreutz et al, 2013). We have also demonstrated that Aβ alters AChE glycosylation in vivo (Sberna et al, 1998;Fodero et al, 2002), and this change is similar to the change in the glycosylation pattern of AChE in AD brain 1999;.…”

Phosphorylation of the Amyloid-Beta Peptide Inhibits Zinc-Dependent Aggregation, Prevents Na,K-ATPase Inhibition, and Reduces Cerebral Plaque Deposition

“…By contrast, phosphorylation at Ser8 may change the interaction of Aβ with other proteins, such as Na + ,K + -ATPase. Previously, it was shown that Na + ,K + -ATPase activity was inhibited in post-mortem tissues of AD patients and in amyloid-containing hippocampi of transgenic mice (but not in the amyloid-free cerebellum) (Dickey et al, 2005; Kreutz et al, 2013; Zhang et al, 2013). The latest studies demonstrated that Aβ 42 in form of monomers or oligomers directly binds to Na + ,K + -ATPase, which results in the inhibition of the enzyme as well as the triggering of intracellular signaling cascades (Ohnishi et al, 2015; Petrushanko et al, 2016).…”