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Alterations in the rate and accuracy of messenger RNA (mRNA) translation are associated with aging and several neurodegenerative disorders, including Alzheimer's disease and related tauopathies. We previously reported that error‐containing RNA that are normally cleared via nonsense‐mediated mRNA decay (NMD), a key RNA surveillance mechanism, are translated in the adult brain of a Drosophila model of tauopathy. In the current study, we find that newly‐synthesized peptides and translation machinery accumulate within nuclear envelope invaginations that occur as a consequence of tau pathology, and that the rate of mRNA translation is globally elevated in early stages of disease in adult brains of Drosophila models of tauopathy. Polysome profiling from adult heads of tau transgenic Drosophila reveals the preferential translation of specific mRNA that have been previously linked to neurodegeneration. Unexpectedly, we find that panneuronal elevation of NMD further elevates the global translation rate in tau transgenic Drosophila, as does treatment with rapamycin. As NMD activation and rapamycin both suppress tau‐induced neurodegeneration, their shared effect on translation suggests that elevated rates of mRNA translation are an early adaptive mechanism to limit neurodegeneration. Our work provides compelling evidence that tau‐induced deficits in NMD reshape the tau translatome by increasing translation of RNA that are normally repressed in healthy cells. [ABSTRACT FROM AUTHOR]

• Arc1 multimers are elevated in the brain of tau transgenic Drosophila • Arc1-overexpressing neurons are enriched with phospho-tau. • Arc1 is elevated in nuclei and the synapse-dense neuropil in tau transgenic flies. • Arc1 is a genetic modifier of neurotoxicity in tau transgenic Drosophila. Alzheimer's disease and other tauopathies are neurodegenerative disorders pathologically defined by aggregated forms of tau protein in the brain. While synaptic degradation is a well-established feature of tau-induced neurotoxicity, the underlying mechanisms of how pathogenic forms of tau drive synaptic dysfunction are incompletely understood. Synaptic function and subsequent memory consolidation are dependent upon synaptic plasticity, the ability of synapses to adjust their structure and strength in response to changes in activity. The activity regulated cytoskeleton associated protein ARC acts in the nucleus and at postsynaptic densities to regulate various forms of synaptic plasticity. ARC harbors a retrovirus-like Gag domain that facilitates ARC multimerization and capsid formation. Trans-synaptic transfer of RNA-containing ARC capsids is required for synaptic plasticity. While ARC is elevated in brains of patients with Alzheimer's disease and genetic variants in ARC increase susceptibility to Alzheimer's disease, mechanistic insight into the role of ARC in Alzheimer's disease is lacking. Using a Drosophila model of tauopathy, we find that pathogenic tau significantly increases multimeric species of the protein encoded by the Drosophila homolog of ARC , Arc1 , in the adult fly brain. We find that Arc1 is elevated within nuclei and the neuropil of tau transgenic Drosophila , but does not localize to synaptic vesicles or presynaptic terminals. Lastly, we find that genetic manipulation of Arc1 modifies tau-induced neurotoxicity, suggesting that tau-induced Arc1 elevation mediates neurodegeneration. Taken together, our results suggest that ARC elevation in human Alzheimer's disease is a consequence of tau pathology and is a causal factor contributing to neuronal death. [ABSTRACT FROM AUTHOR]

Introduction: While brains of patients with Alzheimer's disease and related tauopathies have evidence of altered RNA processing, we lack a mechanistic understanding of how altered RNA processing arises in these disorders and if such changes are causally linked to neurodegeneration. Methods: Using Drosophila melanogaster models of tauopathy, we find that overall activity of nonsense‐mediated mRNA decay (NMD), a key RNA quality‐control mechanism, is reduced. Genetic manipulation of NMD machinery significantly modifies tau‐induced neurotoxicity, suggesting that deficits in NMD are causally linked to neurodegeneration. Mechanistically, we find that deficits in NMD are a consequence of aberrant RNA export and RNA accumulation within nuclear envelope invaginations in tauopathy. We identify a pharmacological activator of NMD that suppresses neurodegeneration in tau transgenic Drosophila, indicating that tau‐induced deficits in RNA quality control are druggable. Discussion: Our studies suggest that NMD activators should be explored for their potential therapeutic value to patients with tauopathies. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease (AD) is a complex multifaceted disease that is mediated by multiple unidentified genetic and environmental factors. One such factor that has been implicated, but is yet to be fully understood, is the role of transposable elements (TE) in AD. Here, we explore the role and scope of TEs using genetically diverse population of mice carrying familial AD mutations (AD‐BXDs) and their non‐transgenic littermates (Ntg‐BXDs). Method: We quantified the expression levels of all known transposable elements (TEs) in the hippocampus using TEtranscripts (v.0.36) in 28 different mouse strains carrying familial AD mutations (AD‐BXDs) and in their non‐transgenic littermates (Ntg‐BXDs) at 6 and 14 months of age. Differentially abundant TEs as a function of genotype (Ntg vs 5XFAD) and age (6m vs 14m) were assessed using DESeq2. We assessed heritability of TE expression for TEs that were identified as significantly differential expressed from the above comparisons, to obtain an estimate of heritable variation in a genetically diverse population. Lastly, we correlated TE expression to short‐term and long‐term memory using contextual fear conditioning. Result: Differential expression analysis revealed higher number of differentially expressed TEs in the 14‐month age group between AD‐BxD and their Ntg littermate controls as compared to the 6‐month age group. Majority of these differentially expressed TE are upregulated and belong to the category of LTR transposons. Importantly, we observe high average heritable variation (h26m‐Ntg=0.65, h26m‐5xFAD=0.58, h214m‐Ntg =0.44, h214m‐5xFAD=0.79) across our genetically diverse AD‐BXD panel. Lastly, we find significant negative correlations among contextual fear conditioning phenotypes and TE expression in the 5XFAD genotype group in both our 6m and 14m age groups. Conclusion: Our findings reveal a role of transposable elements, particularly LTR transposons across our genetically diverse population of mice, specifically in our 14m 5xFAD cohort. This finding is in line with previously published studies of the prevalence of LTR transposons in tauopathy models but is the first to assess the abundance and report on the extent of heritable variation of TE along with their correlation to cognitive behavior in a genetically diverse but translationally relevant mouse population of human AD. [ABSTRACT FROM AUTHOR]

Introduction: While brains of patients with Alzheimer's disease and related tauopathies have evidence of altered RNA processing, we lack a mechanistic understanding of how altered RNA processing arises in these disorders and if such changes are causally linked to neurodegeneration., Methods: Using Drosophila melanogaster models of tauopathy, we find that overall activity of nonsense-mediated mRNA decay (NMD), a key RNA quality-control mechanism, is reduced. Genetic manipulation of NMD machinery significantly modifies tau-induced neurotoxicity, suggesting that deficits in NMD are causally linked to neurodegeneration. Mechanistically, we find that deficits in NMD are a consequence of aberrant RNA export and RNA accumulation within nuclear envelope invaginations in tauopathy. We identify a pharmacological activator of NMD that suppresses neurodegeneration in tau transgenic Drosophila, indicating that tau-induced deficits in RNA quality control are druggable., Discussion: Our studies suggest that NMD activators should be explored for their potential therapeutic value to patients with tauopathies., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)