Abstract
Alzheimer’s disease (AD) is characterised by Aβ and tau pathology as well as synaptic degeneration, which correlates best with cognitive impairment. Previous work suggested that this pathological complexity may result from changes in mRNA translation. Here, we studied whether mRNA translation and its underlying signalling are altered in an early model of AD, and whether modelling this deficiency in mice causes pathological features with ageing. Using an unbiased screen, we show that exposure of primary neurons to nanomolar amounts of Aβ increases FMRP-regulated protein synthesis. This selective regulation of mRNA translation is dependent on a signalling cascade involving MAPK-interacting kinase 1 (Mnk1) and the eukaryotic initiation factor 4E (eIF4E), and ultimately results in reduction of CYFIP2, an FMRP-binding protein. Modelling this CYFIP2 reduction in mice, we find age-dependent Aβ accumulation in the thalamus, development of tau pathology in entorhinal cortex and hippocampus, as well as gliosis and synapse loss in the hippocampus, together with deficits in memory formation. Therefore, we conclude that early stages of AD involve increased translation of specific CYFIP2/FMRP-regulated transcripts. Since reducing endogenous CYFIP2 expression is sufficient to cause key features of AD with ageing in mice, we suggest that prolonged activation of this pathway is a primary step toward AD pathology, highlighting a novel direction for therapeutic targeting.
Highlights
Amyloid-β (Aβ) plaques[1] and phosphorylated tau tangles[2] are classical histological features found in brains of patients suffering from Alzheimer’s disease (AD), a neurodegenerative condition that causes loss of memory and other cognitive impairments in older age[3,4]
To determine which mRNAs might be regulated at the level of translation by Aβ1-42 treatment, we performed paired RNA sequencing in total cytosolic extracts and ribosomal-enriched fractions using sucrose cushions (Fig. 1c) from rat cortical neurons treated for 24 h with Aβ1-42 or vehicle
We studied whether the dissociation of eukaryotic initiation factor 4E (eIF4E) and CYFIP2 could lead to reduction of CYFIP2 expression, using immunoblotting to detect CYFIP2 levels in cell lysates which were normalised to levels of a neuronal marker, neuron specific enolase (NSE)
Summary
Amyloid-β (Aβ) plaques[1] and phosphorylated tau tangles[2] are classical histological features found in brains of patients suffering from Alzheimer’s disease (AD), a neurodegenerative condition that causes loss of memory and other cognitive impairments in older age[3,4]. The best correlate of memory loss is the progressive degeneration of synapses, which occurs prior to neuronal death[5]. Changes in Aβ metabolism may result in synaptic degeneration via the production of soluble Aβ1-42 oligomers[6,7], a consequence of excessive amyloidogenic processing of the amyloid precursor protein (APP)[8]. Aβ1-42 oligomers have been suggested to locally stimulate the synthesis of APP at synapses, via an mRNA translation-dependent mechanism that involves the RNA-. Binding protein fragile X mental retardation protein (FMRP)[9,10]. In this manner, Aβ1-42 may drive its own production, resulting in a feed-forward loop of toxicity at a vulnerable location. FMRP binds to hundreds of mRNAs in the brain, including App mRNA11–13
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
