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Control of protein manufacture at the point of translation is a crucial step in the regulation of gene expression and has shown to be important to many neurological processes, for example, synaptic plasticity and memory formation. The aim of this review was to discuss aberrant translation of proteins implicated in Alzheimer’s disease pathology. Discussion Aberrant translation has been linked with neurodegenerative conditions such as Alzheimer’s disease; however, it is not fully understood how this aberrant protein synthesis occurs or how this may be sustained in Alzheimer’s disease. Cell stressors such as oxidative stress may enhance the translation of Alzheimer’s disease– associated proteins (e.g. amyloid precursor protein), and new research suggests that the cell survival response (e.g. elF2-alpha phosphorylation) may inadvertently up-regulate the translation of proteins such as BACE1; a process mediated in this instance by an upstream open reading frame located within the BACE1 5’UTR. Conclusion The research discussed in this review article has identified that in addition to regulation at the point of transcription and post-translational protein processing, the levels of proteins which negatively associate with Alzheimer’s disease pathology may also be controlled at the point of translation. Stressors such as oxidative stress may drive the transcription of amyloid precursor protein and the cleavage of amyloid precursor protein and may also enhance the translational efficiency of both amyloid precursor protein and the secretase responsible for cleaving amyloid precursor protein into its cytotoxic Abeta42 fragment. We suggest that selectively inhibiting the translation machinery in combination with reducing the levels of oxidative stress may represent a new therapeutic avenue for the treatment of Alzheimer’s disease. Introduction Translation Gene expression comprises a series of complex and tightly regulated events, starting with transcription and ending with protein synthesis. In a simple model, translation initiation of messenger RNA begins when the cap-binding protein complex is recruited to the cap complex. This complex then scans the 5’UTR of the messenger RNA in a 5ʹ to 3ʹ direction until a start codon is recognised and synthesis is initiated (reviewed in depth by Jackson et al.1); the process of translation then progresses through three stages: initiation, elongation, and termination. The cap-binding complex that forms at the initiation step is an assembly of a multitude of translation initiation factors, while the 5’-untranslated region (5’UTR) may differ in length, possess features such as tertiary structures, upstream open reading frames (uORFs) and RNA proteinbinding sites2–4. Importantly, each feature may act as a regulatory element independently enhancing or repressing the rate of protein synthesis (see Jackson et al.1). Transcription and mRNA processing can be a lengthy process; therefore regulation of gene expression at the point of transcription may be insufficiently rapid to function as a responder to a stimuli or stress. One hypothesis suggests that the cell can overcome this constraint by transcribing reservoirs of inactive messages that remain dormant awaiting translational activation only when protein is required—an idea supported by data showing that mRNA levels only partly correlate with protein levels5. This model allows for transcripts to be ‘activated’, then proteins rapidly synthesised from stored templates. It is unsurprising that most detailed investigations into the regulation of translation have focussed on the area of stress responses, where the rate of protein manufacture may directly determine cell survival. However, recent research has also identified this step in the gene expression pathway to be a key stage of control in the manufacture of proteins linked with the pathology of progressive neurodegenerative conditions such as Alzheimer’s disease (AD). The aim of this review was to discuss new and exciting research that identifies putative mechanisms of regulation of proteins associated with AD. Discussion The authors have referenced some of their own studies in this review. The protocols of these studies have been approved by the relevant ethics committees related to the institution in which they were performed. * Corresponding author Email: Andrew.bottley@nottingham.ac.uk; Alexander.kondrashov@nottingham.ac.uk 1 School of Biosciences, University of Nottingham, Nottingham, UK 2 School of Medicine, University of Nottingham, Nottingham, UK

Aberrant translation of proteins implicated in Alzheimer�s disease pathology