ABSTRACT
Alzheimer's disease contributes to 60-70% of all dementia cases in the general population. Belonging to the BIN1/amphiphysin/RVS167 (BAR) superfamily, the bridging integrator (BIN1) has been identified to impact two major pathological hallmarks in Alzheimer's disease (AD), i.e., amyloid beta (Aß) and tau accumulation. Aß accumulation is found to increase by BIN1 knockdown in cortical neurons in late-onset AD, due to BACE1 accumulation at enlarged early endosomes. Two BIN1 mutants, KR and PL, were identified to exhibit Aß accumulation. Furthermore, BIN1 deficiency by BIN1-related polymorphisms impairs the interaction with tau, thus elevating tau phosphorylation, altering synapse structure and tau function. Even though the precise role of BIN1 in the neuronal tissue needs further investigation, the authors aim to throw light on the potential of BIN1 and unfold its implications on tau and Aß pathology, to aid AD researchers across the globe to examine BIN1, as an appropriate target gene for disease management.
Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Amyloid Precursor Protein Secretases/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Aspartic Acid Endopeptidases/metabolism , tau Proteins/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
Type 2 diabetes (T2D) is one of the most widely spread metabolic disordersand is also referred as a 'lifestyle' disorder. According toa study conducted by IDB, the number of individuals affected with diabetes is expected to increase from 463 to 700 million by the end of year 2045. Thus, there is a great need to developed targeted therapies that can maintain homeostasis of glucose levels and improving insulin sensitivity which can overcome hurdles associated with conventional medicine. Detailed analysis was conducted by analyzing various research and review papers which were searched using MEDLINE and EMBASE using various keywords. This search retrieved the most appropriate content on these molecules targeting Nrf-2 functions and Nrf-2 pathway associated with diabetic neuropathy and nephropathy. In this review article, we have highlighted the role of Nrf-2 in diabetic associated complications of neuropathy and nephropathy. Since hyperglycemia is associated with oxidative stress and inflammation, regulating Nrf-2 activity through various synthetic and natural activators whichmay provide therapeutic benefits for the treatment and mitigation of diabetic neuropathy and nephropathy as well. Based on the available literature on Nrf-2 activity and despite some controversies in the association of Nrf-2 activity and its therapeutic usage, it can be concluded that regulation of this pathway is a trigger in the development of diabetes-associated complications. Thus, targeting this pathway with various activators may emerge as a novel therapy in the treatment of diabetes and diabetes-associated complications. Nrf-2 activation leading to regulation of various downstream pathways responsible for managament of Diabetic neuropathy and nephropathy Legend: Activities regulated by the activation of Nrf-2 pathway by Natural and Synthetic activators. Various downstream signalling pathway are involved in increase (+) and decrease (-) in levels of Nrf-2 levels. Subsequently controlling various mechanism involved in the pathogenies of Diabetic neuropathy and nephropathy.
