4 of these miRNAs are also upregulated in AD patients. Conclusionĭiverging AD-related neuropathologies induce common disturbances in the expression of neuronal miRNAs. Upregulating these miRNAs in wild-type mice is however not causing AD-related cognitive disturbances. All 6 miRNAs are strongly enriched in neurons. Six miRNAs (miR-10a-5p, miR-142a-5p, miR-146a-5p, miR-155-5p, miR-211-5p, miR-455-5p) are commonly upregulated between APPtg and TAUtg mice, and four of these (miR-142a-5p, miR-146a-5p, miR-155-5p and miR-455-5p) are altered in AD patients. Behavior of wild-type mice was assessed after intracerebroventricular infusion of miRNA mimics. Functional annotation of predicted targets was performed using GO enrichment. Fluorescent in situ hybridization identified their cellular expression. Results were confirmed by qPCR in a separate cohort of 4 M and 10 M APPtg and APPwt mice ( n = 7–9 per group) and in human sporadic AD and non-demented control brain. We analyzed the hippocampi of 12 mice per experimental group ( n = 96 in total), and employed a 2-way linear model to extract differentially expressed miRNAs. MiRNAseq was performed on cognitively intact (4 months) and impaired (10 months) male APPtg (APP swe/PS1 L166P) and TAUtg (THY-Tau22) mice and their wild-type littermates (APPwt and TAUwt). MicroRNA (miRNA) deregulation is well established in AD brain but it is unclear whether Aβ or TAU pathology drives those alterations and whether miRNA changes contribute to cognitive decline. Despite diverging levels of amyloid-β (Aβ) and TAU pathology, different mouse models, as well as sporadic AD patients show predictable patterns of episodic memory loss.

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