Ribonucleoprotein Therapy in Alzheimer's Disease?

Alzheimer's and Parkinson's diseases are accelerated by a decline in neuronal homeostasis. In this issue of Cell Reports, Kang et al. [1] reports the post-transcriptional mechanisms that regulate the expression and processing of amyloid precursor protein (APP), a protein directly implicated in the pathogenesis of Alzheimer's disease (AD). Although much is known about APP processing and cleavage, the post-transcriptional steps controlling APP biosynthesis are poorly defined. The important advance by Kang et al. 2014 is discovering that a single RNA-binding protein (RBP), HuD, binds to APP mRNA and enhances its stability and translation in cells of neuronal origin, stabilizes BACE1 mRNA, encoding the β-site APP-cleaving enzyme 1 (BACE1), and stabilizes BACE1 antisense (BACE1AS), a long noncoding (lnc) RNA that protects BACE1 mRNA from degradation. The positive influence of HuD on these RNAs and the encoded proteins was documented in the brains of mice overexpressing HuD as well as in patients with Alzheimer's Disease, and was linked to the accumulation of the toxic APP cleavage product Aβ in these systems. The results underscore a novel function for HuD in neurodegeneration through its regulation of RNA targets controlling Aβ production. Given its joint influence on three functionally linked RNAs (APP mRNA, BACE1 mRNA, and BACE1AS), that contribute to generating the neurotoxic peptide Aβ, HuD emerges from the studies by Kang and colleagues as a single factor that promotes APP processing to Aβ. Such a coordinated influence on a cellular function by a single RBP represents an example of the post-transcriptional operon/regulon proposed by Keene and Tenenbaum [2]. Besides orchestrating Aβ production, HuD was previously shown to repress translation of another target transcript, the insulin (INS) mRNA [3]. Accordingly, HuD-overexpressing mice exhibited an impaired ability to respond to a glucose challenge [3], a hallmark of diabetes, another pathology that escalates with age. Given that the same RBP, HuD, is linked to neurodegeneration and to diabetes, there is growing interest in modulating HuD expression and/or function. The microRNA miR-375 represses HuD production by lowering the stability and translation of the mRNA that encodes HuD (ELAVL4 mRNA) [4]. In this regard, the Editorial decreased β-cell mass exhibited by miR-375-null mice [5] is a provocative finding, although this phenotype has not yet been linked to the effects of miR-375 upon HuD in the pancreas. Whether miR-375-null mice have also displays increased HuD, APP, BACE1, Bace1as, and Aβ also remains to be studied. The microRNA miR-485, which …