Amyloid-β-Acetylcholinesterase complexes potentiate neurodegenerative changes induced by the Aβ peptide. Implications for the pathogenesis of Alzheimer's disease

Abstract

The presence of amyloid-β (Aβ) deposits in selected brain regions is a hallmark of Alzheimer's disease (AD). The amyloid deposits have "chaperone molecules" which play critical roles in amyloid formation and toxicity. We report here that treatment of rat hippocampal neurons with Aβ-acetylcholinesterase (Aβ-AChE) complexes induced neurite network dystrophia and apoptosis. Moreover, the Aβ-AChE complexes induced a sustained increase in intracellular Ca2+ as well as a loss of mitochondrial membrane potential. The Aβ-AChE oligomers complex also induced higher alteration of Ca2+ homeostasis compared with Aβ-AChE fibrillar complexes. These alterations in calcium homeostasis were reversed when the neurons were treated previously with lithium, a GSK-3β inhibitor; Wnt-7a ligand, an activator for Wnt Pathway; and an N-methyl-D-aspartate (NMDA) receptor antagonist (MK-801), demonstrating protective roles for activation of the Wnt signaling pathway as well as for NMDA-receptor inhibition. Our results indicate that the Aβ-AChE complexes enhance Aβ-dependent deregulation of intracellular Ca2+ as well as mitochondrial dysfunction in hippocampal neurons, triggering an enhanced damage than Aβ alone. From a therapeutic point of view, activation of the Wnt signaling pathway, as well as NMDAR inhibition may be important factors to protect neurons under Aβ-AChE attack.

Antioxidant and anti-cholinesterase activity ofSargassum wightii

“…Moreover, the AChE gets infused stereotaxically into CA1 region of the rat hippocampus and induces the formation of plaque-like structures and directly promotes the deposition of Ab plaques. More recently, it has been demonstrated that Ab-AChE complexes are more toxic than Ab fibrils alone and neurons treated with Ab-AChE complex showed a neurite network more highly disrupted than one treated with Ab alone (Dinamarc et al, 2010). In addition to that, the activity of BuChE has been found to be increased during the later stages of plaque maturation, which subsequently results in neuronal degeneration (Guillozet et al, 1997).…”

In vitroantioxidant and anti-cholinesterase activities ofRhizophora mucronata

“…Experimental evidences illustrate that AChE accelerates aggregation of Ab peptide and formation of Ab-AChE complex at the synaptic region of hippocampus leading to DOI: 10.3109/13880209.2015.1017886 neuronal degeneration (Dinamarca et al, 2010;Reyes et al, 2004). Symptomatic treatment for AD involves potentiation of cholinergic activity through the inhibition of AChE (Rahman & Choudhary, 2001).…”

“…Moreover, Wu et al (2012) reported the blood-brain permeability of catechins, which illustrates that catechins can act as drug for the treatment of AD. Scientific evidences have illustrated AChE inhibitor as most viable therapeutic target for symptomatic improvement in AD because AChE not only enhances the cholinergic neurotransmission in the brain but also reduce the aggregation of b-amyloid, the key factor in AD (Dinamarca et al, 2010). Recent reports have showed that in addition to cholinergic deficit, oxidative stress also plays a pivotal role in the cognitive impairment of AD.…”

Discovery of butyrylcholinesterase inhibitors among derivatives of azaphenothiazines

“…Several in vivo experiments indicated that BuChE is able to compensate for the lack of AChE, enabling continued regulation of cholinergic neurotransmission 19,20 . It has also been shown that cholinesterases display several non-classical properties associated with Ab and neurofibrillary tangles, and are therefore important for AD pathogenesis [21][22][23][24][25] . Recent studies have shown that BuChE exerts an influence on the modulation of motor control, awareness, cognition and behavior by regulation of ACh levels in the central nervous system (CNS) 26 .…”