Novel natural plant protein and mimetic peptides rescues aberrant brain‐energy metabolism and Alzheimer’s disease pathology

Abstract

AbstractBackgroundExtensive evidence has indicated that a high rate of cholesterol biogenesis and abnormal neuronal energy metabolism play key roles in Alzheimer’s disease (AD) pathogenesis. Here, for the first time, we used protein and peptide, a plant protein homolog of mammalian adiponectin, to determine its therapeutic efficacy in different AD models.MethodMice were grouped before treatment as follows: WT and Transgenic mice (APP/PS1 and Adipo‐/‐ mice) were administered via intraperitoneal injection with 3 types of solution (saline, osmotin and osmotin mimetic peptide). Mice were decapitated at the age of 5, 9, 12 or 16 months. Protein samples were analyzed by immunobloting as well as immunofluorescence. Brain sections were analyzed by immune histochemistry. LTP was measured by mEPSC.ResultOsmotin, natural plant protein, and its mimetic peptide treatment modulated adiponectin receptor 1 (AdipoR1), significantly induced AMPK/SIRT1 activation, and reduced SREBP2 expression in both in vivo and in vitro AD and Adiponectin deficient mice. Osmotin acts Via AdipoR1/AMPK/SIRT1/SREBP2 and TNFR1 signaling pathway, Osmotin and its mimetic peptide significantly diminished amyloidogenic Aβ production, abundance and aggregation, accompanied by improved pre‐ and post‐synaptic dysfunction, cognitive impairment, memory deficits. Most importantly, it reversed the suppression of long‐term potentiation (LTP) in AD mice. Interestingly, AdipoR1, AMPK, and SIRT1 silencing not only abolished Osmotin capability but also further enhanced AD pathology by increasing SREBP2, APP, and β‐secretase (BACE1) expression and the levels of toxic Aβ production. Likewise, mimetic peptide mechanistically instigates AdipoR1/AMPK signaling and consequently suppressed the hyperactivated TNF‐α/TNFR1 signaling in both in vivo and in vitro models of AD.ConclusionOsmotin and its mimetic peptide mitigate aberrant brain‐energy metabolism and AD pathology in in vivo and in vitro AD models via regulating AdipoR1/AMPK/SIRT1/SREBP2/TNFR1 signaling pathway. These results suggest that Osmotin and peptide‐based mimetics can be a potential candidate for AD treatment.