Cap‐Independent Translation as a Physiological Process Linking Amyloid and Tau Pathology in Alzheimer’s Disease

Abstract

AbstractBackgroundNeurodegenerative diseases are complex entities that are driven by multiple pathophysiological processes. Alzheimer’s disease (AD) is no exception, with both a multifaceted etiology, and varied pathologies that interact in overlapping ways. Although AD is the most common form of dementia found in the elderly, it is typically encountered with multiple age‐related co‐morbidities that are indicative of other disease processes that likely contribute to the overall neurologic disease state, such as cerebrovascular pathology. A well known connection exists between type 2 diabetes (T2D), or metabolic dysfunction in general, and risk of dementia later in life. Our data indicate that a significant contributing factor that connects these processes may be the increased utilization of cap‐independent translation (CIT), an alternative form of eukaryotic protein manufacture that is more active during various forms of physiologic stress.MethodThrough an investigation of AD cases and controls, multiple cell lines (N2A, CHO, HEK293T, H4), rat primary neurons, cell free transcription / translation assays, and mouse models, we demonstrate that changes in CIT may drive both amyloid and tau pathology.ResultWe found that increased BACE1 protein in AD cases, as well as in vitro, was directly connected to an increase in an mRNA binding protein (ZNF9) responsible for controlling cap‐independent translation. Up and down regulation of ZNF9 produced corresponding changes in BACE1 protein (but not BACE1 mRNA), as well as BIN1, a key driver in the development of tau pathology. Cell free in vitro transcription / translation assays, mRNA binding in vitro and in vivo (both gel shift and RNA immunoprecipitation), and fluorescent reporter assays using a variety of constructs confirmed that ZNF9 is controlling CIT and likely not acting via typical cap‐dependent translation, or by affecting transcription. Additional studies in cell lines, as well as in a mouse model of metabolic dysfunction and amyloid pathology, demonstrated that this process can be driven by metabolic stress.ConclusionIn addition to any direct connection between the development of amyloid‐beta and tau neuropathologies, these data indicate that these two primary pathologic hallmarks of AD could share an upstream connection through a basic, yet underappreciated, biological process.