Tetrahydrohyperforin prevents cognitive deficit, Aβ deposition, tau phosphorylation and synaptotoxicity in the APPswe/PSEN1ΔE9 model of Alzheimer's disease: a possible effect on APP processing

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-β peptide (Aβ) accumulation and synaptic alterations. Previous studies indicated that hyperforin, a component of the St John's Wort, prevents Aβ neurotoxicity and some behavioral impairments in a rat model of AD. In this study we examined the ability of tetrahydrohyperforin (IDN5607), a stable hyperforin derivative, to prevent the cognitive deficit and synaptic impairment in an in vivo model of AD. In double transgenic APPswe/PSEN1ΔE9 mice, IDN5706 improves memory and prevents the impairment of synaptic plasticity in a dose-dependent manner, inducing a recovery of long-term potentiation. In agreement with these findings, IDN5706 prevented the decrease in synaptic proteins in hippocampus and cortex. In addition, decreased levels of tau hyperphosphorylation, astrogliosis, and total fibrillar and oligomeric forms of Aβ were determined in double transgenic mice treated with IDN5706. In cultured cells, IDN5706 decreased the proteolytic processing of the amyloid precursor protein that leads to Aβ peptide generation. These findings indicate that IDN5706 ameliorates AD neuropathology and could be considered of therapeutic relevance in AD treatment.

Dysregulation of neuronal calcium homeostasis in Alzheimer's disease – A therapeutic opportunity?

“…Brain overexpression of TRPC6 channels resulted in spine proliferation and enhanced memory performance in transgenic mice [80], suggesting a potential role for TRPC6 in mediating nSOC. Interestingly, TRPC6 is activated by hyperforin [81] and it has been demonstrated in the previous studies that hyperforin and its derivatives were able to prevent beta-amyloid neurotoxicity and spatial memory impairments in AβPPSwe/PSEN1 E9 (AβPP/PS1) transgenic mice [82–84]. TRPC6 was also recently demonstarted to interact directly with APP and to affect APP cleavage by γ-secretase [85].…”

Interactions of AChE with A? Aggregates in Alzheimer?s Brain: Therapeutic Relevance of IDN 5706

“…When aggregation experiments were carried and repeated in the presence of AChE inhibitors (AChEIs) directed against the two different sites, it turned out that only the PAS inhibitors were able to block the effect of AChE on amyloid formation (Alvarez et al, 1998). The PAS inhibitors, propidium and fasciculin, were able to prevent the effect of AChE on Aβ aggregation process (Bartolini et al, 2003; Inestrosa et al, 2008). On the other hand, the amyloid aggregation in the presence of edrophonium, an active site inhibitor of AChE, showed no effect on the role of AChE in this capacity to accelerate Aβ assembly into Alzheimer’s fibrils (Inestrosa et al, 2008).…”

Hyperforin: To Be or Not to Be an Activator of TRPC(6)

“…The effects were significantly reduced by the unselective TRP channel blocker La 3+ ). Several recent publications point to an improvement of cognition in different animals models for Alzheimer's disease and a reduction of amyloid beta plaques, one of the hallmarks of Alzheimer's disease by St. John's wort extract, hyperforin, or tetrahyperforin (Dinamarca et al 2006;Cerpa et al 2010;Griffith et al 2010;Carvajal and Inestrosa 2011;Inestrosa et al 2011;Abbott et al 2013;Carvajal et al 2013;Brenn et al 2014;Montecinos-Oliva et al 2014). Tetrahyperforin was also shown to improve adult neurogenesis in wild-type as well as a transgenic Azheimer's animal model (Abbott et al 2013) as well as a reduction of synaptotoxicity (Montecinos-Oliva et al 2015).…”