Alzheimer's disease (AD) is characterized by progressive memory loss and cognitive function deficits. There are two major pathological hallmarks that contribute to the pathogenesis of AD which are the presence of extracellular amyloid plaques composed of amyloid-β (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Despite extensive research that has been done on Aβ in the last two decades, therapies targeting Aβ were not very fruitful at treating AD as the efficacy of Aβ therapies observed in animal models is not reflected in human clinical trials. Hence, tau-directed therapies have received tremendous attention as the potential treatments for AD. Tauopathies are closely correlated with dementia and immunotherapy has been effective at reducing tau pathology and improving cognitive deficits in animal models. Thus, in this review article, we discussed the pathological mechanism of tau proteins, the key factors contributing to tauopathies, and therapeutic approaches for tauopathies in AD based on the recent progress in tau-based research.
Emerging findings point toward an important interconnection between epilepsy and Alzheimer's disease (AD) pathogenesis. Patients with epilepsy (PWE) commonly exhibit cognitive impairment similar to AD patients, who in turn are at a higher risk of developing epilepsy compared to age-matched controls. To date, no disease-modifying treatment strategy is available for either epilepsy or AD, reflecting an immediate need for exploring common molecular targets, which can delineate a possible mechanistic link between epilepsy and AD. This review attempts to disentangle the interconnectivity between epilepsy and AD pathogenesis via the crucial contribution of Tau protein. Tau protein is a microtubule-associated protein (MAP) that has been implicated in the pathophysiology of both epilepsy and AD. Hyperphosphorylation of Tau contributes to the different forms of human epilepsy and inhibition of the same exerted seizure inhibitions and altered disease progression in a range of animal models. Moreover, Tau-protein-mediated therapy has demonstrated promising outcomes in experimental models of AD. In this review, we discuss how Tau-related mechanisms might present a link between the cause of seizures in epilepsy and cognitive disruption in AD. Untangling this interconnection might be instrumental in designing novel therapies that can minimize epileptic seizures and cognitive deficits in patients with epilepsy and AD.
Alzheimer's disease (AD) is the most common cause of dementia. The cardinal neuropathological characteristic of AD is the accumulation of amyloid-β (Aβ) into extracellular plaques that ultimately disrupt neuronal function and lead to neurodegeneration. One possible therapeutic strategy therefore is to prevent Aβ aggregation. Previous studies have suggested that vitamin E analogs slow AD progression in humans. In the present study, we investigated the effects of the tocotrienol-rich fraction (TRF), a mixture of vitamin E analogs from palm oil, on amyloid pathology in vitro and in vivo. TRF treatment dose-dependently inhibited the formation of Aβ fibrils and Aβ oligomers in vitro. Moreover, daily TRF supplementation to AβPPswe/PS1dE9 double transgenic mice for 10 months attenuated Aβ immunoreactive depositions and thioflavin-S-positive fibrillar type plaques in the brain, and eventually improved cognitive function in the novel object recognition test compared with control AβPPswe/PS1dE9 mice. The present result indicates that TRF reduced amyloid pathology and improved cognitive functions, and suggests that TRF is a potential therapeutic agent for AD.
We have recently shown that the tocotrienol-rich fraction (TRF) of palm oil, a mixture of vitamin E analogs, improves amyloid pathology in vitro and in vivo. However, precise mechanisms remain unknown. In this study, we examined the effects of long-term (10 months) TRF treatment on behavioral impairments and brain metabolites in (15 months old) AβPP/PS1 double transgenic (Tg) Alzheimer's disease (AD) mice. The open field test, Morris water maze, and novel object recognition tasks revealed improved exploratory activity, spatial learning, and recognition memory, respectively, in TRF-treated Tg mice. Brain metabolite profiling of wild-type and Tg mice treated with and without TRF was performed using ultrahigh performance liquid chromatography (UHPLC) coupled to high-resolution accurate mass (HRAM)-orbitrap tandem mass spectrometry (MS/MS). Metabolic pathway analysis found perturbed metabolic pathways that linked to AD. TRF treatment partly ameliorated metabolic perturbations in Tg mouse hippocampus. The mechanism of this pre-emptive activity may occur via modulation of metabolic pathways dependent on Aβ interaction or independent of Aβ interaction.