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.
Highlights
Alzheimer’s disease (AD) is characterized by a progressive deterioration of cognitive abilities, eventually leading to the death of the individual
These results indicate that IDN5706 prevents amyloid-b peptide (Ab) load in the transgenic mouse model
We have demonstrated that 5-month-old amyloid precursor protein (APP)-PS1 mice treated with tetrahydrohyperforin, IDN5706, during 10 weeks did not present decreased cognitive capacities and neuropathological markers of AD as compared with control vehicle-injected APPswe/PSEN1DE9 mice (APP-PS1) mice
Summary
Alzheimer’s disease (AD) is characterized by a progressive deterioration of cognitive abilities, eventually leading to the death of the individual. Accumulation of the amyloid-b peptide (Ab), a product of the processing of the amyloid precursor protein (APP), is believed to have a key role in the cognitive deficits observed in AD.[1] the mechanisms involved in the pathogenic changes triggered by Ab are not clearly understood, the neuronal dysfunction and cytoskeletal alterations are early manifestations that lead to aberrant remodeling of dendrites and axons, synaptic loss,[2] and eventually progressive loss of neuronal populations,[3] which is associated with the appearance of dystrophic neurites and abnormal phosphorylation of cytoskeletal proteins mostly phosphorylation of the microtubule-associated protein tau.[3,4] Besides, analyses of AD mouse models and AD patients brains support the hypothesis that aggregates of Ab are responsible for the ‘synaptic failure’, which occurs before the plaque development and neuronal cell death; such effects are triggered by Ab oligomers, which are soluble and toxic molecular forms of Ab.[5,6] The synaptic failure is correlated with the reduction in synaptic proteins and alterations in synaptic function.[7,8,9,10,11]. Tetrahydrohyperforin (IDN5706) a semi synthetic derivative of hyperforin, with a higher stability and increased oral bioavailability,[15] has shown some neuroprotective properties.[16]
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