Abstract:

To date, there is no therapy to stop the destruction of brain cells and all the available treatments only compensate for the loss of synaptic transmission, thus resulting in marginal benefits to patients. Therefore, there is an urgent need to find effective therapies that prevent or slow down the progression of this major public health problem. To prevent brain cell loss, we need to identify and understand the exact causes of the disease. In the present perspective, we propose that positive regulators of ER autophagy-related responses, such as tetrahydrohyperforin, are promising niches for the discovery of future therapies against AD. A recent study published by our group using a neuroprotective semisynthetic derivative of hyperforin, the active molecule in the St John´s Wort plant (Hypericum perforatum) called tetrahydrohyperforin (IDN5706), has demonstrated that this compound prevents the neuropathological changes in a mouse model of AD. Specifically, it induces long-term potentiation (LTP) and prevents AD-associated loss of spatial memory, reduces tau hyperphosphorylation, and decreases Abeta peptide levels. In an effort to elucidate the molecular mechanism that could explain the beneficial effects of this compound, we recently showed that IDN5706 targets the ER for autophagy activation, triggering entry of immaturely glycosylated, newly-synthesized APP (iAPP) in ER-associated structures, which favors its degradation by Atg5-dependent autophagy, leading to inhibition of Abeta peptide formation. Autophagy, a major lysosomal degradative pathway, has been extensively studied in age-related neurodegenerative disorders, such as AD, due to its strong connection between aging and the progressive deterioration in the proteostatic capacity of the brain. Although, several studies indicate that induction of autophagy delays aging, reducing the risk of neurodegenerative disorders and neuronal dysfunction in animal models, the underlying mechanisms still remain poorly understood. In this context, our recent findings with the neuroprotective compound IDN5706 revealed that the ER could be a major regulator for autophagy activation, necessary to promote the clearance of APP upon perturbations in its glycosylation, strongly supporting the hypothesis that autophagy could play a key role in quality control at the ER.