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

B Barak,E Okun,D M Michaelson,S Modai,N Shomron,M P Mattson,U Ashery,I Shvarts-Serebro,A Gilam

doi:10.1038/tp.2013.77

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.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia in the elderly
Given that each miRNA can regulate several genes,[42,73,74] and that miRNAs are typically transcribed in clusters,[42] we set to test the involvement of miRNAs in post-transcriptional regulation of synaptic transmission and AD pathology
We studied the miRNA regulators that may contribute to the beneficial and detrimental effects of EE and AD, respectively, on synaptic plasticity-related proteins and AD pathology, and explored the modulation of the synaptic protein tomosyn in mouse models of EE and AD

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia in the elderly. Its pathology is associated with extracellular Ab plaques, intracellular tau tangles and cell death in the brain.[1,2,3] Progression of this disease is characterized by cognitive impairment and deterioration of brain performance.[1,3] These devastating processes are associated with loss of neuronal synapses[1] and alterations in synaptic plasticity, and are most pronounced in the hippocampus, entorhinal cortex and default mode network, brain areas that are among the first to be affected in AD.[3,4,5]AD progression is influenced by both genetic and environmental factors,[6,7,8] and gene–environment interactions may influence and trigger pathogenic pathways that determine the severity and progression of the disease.[6,7,8] Interestingly, education and socioeconomic background in humans may affect AD pathogenesis,[9,10] with several epidemiological studies showing that subjects with a lower education level are at higher risk of developing AD.[11]. Its pathology is associated with extracellular Ab plaques, intracellular tau tangles and cell death in the brain.[1,2,3] Progression of this disease is characterized by cognitive impairment and deterioration of brain performance.[1,3] These devastating processes are associated with loss of neuronal synapses[1] and alterations in synaptic plasticity, and are most pronounced in the hippocampus, entorhinal cortex and default mode network, brain areas that are among the first to be affected in AD.[3,4,5]. No cure is currently available for AD, exposure to an enriched environment (EE) has been shown to have a protective effect in mouse models by slowing disease progression and reducing AD-like cognitive impairment,[12,13,14,15,16,17] how exactly EE may be beneficial to AD pathology is yet not fully understood

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Results

Conclusion