Over-expression of miR-34a induces rapid cognitive impairment and Alzheimer’s disease-like pathology

• Published in: Brain research 2019-10, Vol.1721, p.146327-146327, Article 146327
• Main Authors: Sarkar, S., Engler-Chiurazzi, E.B., Cavendish, J.Z., Povroznik, J.M., Russell, A.E., Quintana, D.D., Mathers, P.H., Simpkins, J.W.
• Format: Article
• Language: English
• Subjects: ADAM10; Late-onset Alzheimer’s disease; Memory-related behaviors; microRNA; miR-34a; NMDAR 2B; SIRT1; Tau phosphorylation; β amyloid
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2019.146327

•Sporadic Alzheimer’s disease (sAD) is difficult to model in animals.•We produced a conditional over-expressing, miR-34a mouse to model sAD.•miR-34a over-expression results in a rapid cognitive impairment.•miR-34a over-expression also induces AD pathology in various cognitive brain regions.•Inducible miR-34a mice may represent a polygenetic risk factor model for sAD. Autosomal dominant Alzheimer disease (AD) is caused by rare mutations in one of three specific genes. This is in contrast to idiopathic, late-onset AD (LOAD), which has a more polygenetic risk profile and represents more than 95% of cases. Previously, we have demonstrated that increased expression of microRNA (miRNA)-34a (miR-34a) in AD brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity. Here we report the generation of a heterozygous, conditional miR-34a overexpression mouse (miR-34a+/−(TetR-TetO-miR-34a) Transgenic Mice). Doxycycline-treated mice of either sex exhibited profound behavioral impairment compared to untreated groups with only 1–2 months of over-expression of miR-34a. Cognitive impairment of individual mice in T- and Y-maze tasks correlated with elevated miR-34a expression in many parts of the brain including the hippocampus and prefrontal cortex, regions which are known to be involved in this task and implicated in LOAD dysfunction. Immunocytochemistry of brain sections from mice show high amyloid β and phosphorylated tau-specific staining in the hippocampus and cortex. Analysis of protein samples from these mice revealed that miR-34a targets specific genes involved in memory formation, amyloid precursor protein (APP) metabolism and phosphorylation-dephosphorylation of tau. Thus, our results suggest that the polygenetic dysfunction caused by miR-34a may occur in LOAD and disclose miR-34a as a potential therapeutic target. Late-onset Alzheimer disease (LOAD) is associated with multiple gene alleles, a polygenetic profile of risk factors that is difficult to model in animals. Our approach to modeling LOAD was to produce a conditional over-expressing, miR-34a mouse using doxycycline-induction to activate expression. We observed that miR-34a over-expression results in a rapid cognitive impairment, associated with accumulation of intracellular Aβ and tau hyperphosphorylation in multiple brain regions. Targets for miR-34a, including ADAM10, NMDAR 2B, and SIRT1 RNAs, were profoundly reduced by miR-34a over-expression. Collectively,