Tetrahydrohyperforin Decreases Cholinergic Markers associated with Amyloid-β Plaques, 4-Hydroxynonenal Formation, and Caspase-3 Activation in AβPP/PS1 Mice

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-beta peptide (A beta) accumulation, neurofibrillary tangle deposition, synaptic alterations, and oxidative injury. In AD patients, acetylcholinesterase (AChE) activity is low in most regions of the brain, but increased within and around amyloid plaques, where it accelerates the A beta assembly into oligomers and fibrils, increasing its neurotoxicity. Tetrahydrohyperforin (THH), a semi-synthetic derivative of hyperforin, reduces tau phosphorylation and A beta accumulation in AD mouse models. In the present study, we examined the effects of THH on A beta-AChE complexes, alpha 7-nicotinic acetylcholine receptors (alpha 7-nAChR), 4-hydroxynonenal (4-HNE) adducts, caspase-3 activation, and spatial memory in young A beta PPSwe/PSEN1 Delta E9 (A beta PP/PS1) transgenic mice, in order to evaluate its potential preventive effects on the development of the disease. We report here that treatment with THH prevents the association of AChE to different types of amyloid plaques; partially restores the brain distribution of AChE molecular forms; increases alpha 7-nAChR levels in the hippocampus of treated mice; decreases the amount of these receptors in amyloid plaques; and reduces the oxidative damage, evidenced by 4-HNE adduct formation and caspase-3 activation on A beta PP/PS1 mice brain; demonstrating the neuroprotective properties of THH. Finally, we found that the acute treatment of hippocampal neurons with THH, in the presence of A beta-AChE complexes, prevents 4-HNE adduct formation and caspase-3 activation. Our data support a therapeutic potential of THH for the treatment of AD.