Opposing actions of environmental enrichment and Alzheimer’s disease on the expression of hippocampal microRNAs in mouse models

Abstract

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Although there are no drugs that modify the disease process, exposure to an enriched environment (EE) can slow the disease progression. Here, we characterize the effects of AD and EE on the post-transcriptional regulators, microRNAs (miRNAs), which may contribute to the detrimental and beneficial effects of AD and EE, respectively, on synaptic plasticity-related proteins and AD pathology. We found for the first time miRNAs that were inversely regulated in AD and EE, and may affect synaptic proteins and modulators, molecular factors associated with AD pathology, and survival and neuroprotective factors. MiRNAs that were upregulated only in 3xTgAD mice model of AD compared with their control mice were localized to synapses, predicted to downregulate essential synaptic proteins and are highly associated with regulating apoptosis, AD-associated processes and axon guidance. Studying the progressive change in miRNAs modulation during aging of 3xTgAD mice, we identified miRNAs that were regulated in earlier stages of AD, suggesting them as potential AD biomarkers. Last, we characterized AD- and EE-related effects in the mouse hippocampus on tomosyn protein levels, an inhibitor of the synaptic transmission machinery. While EE reduced tomosyn levels, tomosyn levels were increased in old 3xTgAD mice, suggesting a role for tomosyn in the impairment of synaptic transmission in AD. Interestingly, we found that miR-325 regulates the expression levels of tomosyn as demonstrated by a luciferase reporter assay, and that miR-325 was downregulated in AD and upregulated following EE. These findings improve our understanding of the molecular and cellular processes in AD pathology, following EE, and the interplay between the two processes, and open new avenues for the studies of understanding and controlling AD.

A Combined Optogenetic-Knockdown Strategy Reveals a Major Role of Tomosyn in Mossy Fiber Synaptic Plasticity

“…Tomosyn emerges as an important regulator of both basal synaptic transmission and presynaptic forms of plasticity. In support of this role in vivo is the recent observation that tomosyn levels are down-regulated in animals exposed to enriched environment and up-regulated in an Alzheimer's disease mouse model (Barak et al, 2013b). …”

The role of cognitive activity in cognition protection: from Bedside to Bench

“…MiR-124a showed a similar performance following enriched environment condition [175]. MiR-325 was downregulated in 3 × Tg AD mice but upregulated by EE, which may open new avenues for the studies of treating AD [176]. Until now, this field of exploration is now relatively new, therefore many questions regarding the epigenetic impacts of EE remain unsolved.…”

Loss of miR-369 Promotes Tau Phosphorylation by Targeting the Fyn and Serine/Threonine-Protein Kinase 2 Signaling Pathways in Alzheimer’s Disease Mice

“…For example, Serpente et al (2011) found that miR-369 may affect the occurrence and development of AD via the LDL receptor 1 gene (OLR1, rs1050283). Barak et al (2013) found decreased levels of miR-369 in the hippocampal tissue of the 3xTg-AD mouse brain. Our preliminary experiment also showed a similar phenomenon in 6-month-old 3xTg-AD mice (see Supplementary Figure S1).…”