The potential role of microRNA-146 in Alzheimer’s disease: Biomarker or therapeutic target?
Introduction
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia among the aging population. The neuropathological alterations of AD are characterized by loss of synapses and neurons, intracellular neurofibrillary tangles and extracellular amyloid plaques formation [1]. The classical hypothesis for the cause of AD is aberrant amyloid protein deposition of Aβ42, due to abnormal amyloid precursor protein (APP) processing. Recently, an increasing number of studies indicate that dysfunctions of neuroimmune networks also contribute to the pathogenesis of AD [2], [3], [4], [5].
Physically, the innate system of immunity and inflammatory signaling are critical for brain homeostasis, neuroprotection and repair. Once over-activated, they produce excess oxygen free radicals, pro-inflammatory cytokines, and prostaglandins, subsequently triggering the inflammatory cascade, and result in neurodegeneration. Hence, the inflammatory response is a highly regulated by an extreme complex network of intracellular and extracellular events. Recently, a series of studies demonstrated that microRNAs (miRNAs) can affect mammalian immune cell differentiation, and the subsequent immune responses have been implicated in a wide variety of human brain dysfunctions including AD [6], [7], [8], [9], [10]. The microRNA miR-146 is abundant in both mouse and human brains, and it was first identified as an immune system regulator by expression profiling of 200 miRNAs after exposure of human monocytes to various bacterial components [11]. Furthermore, prior studies pointed out that miR-146 is involved in up-regulated inflammatory signaling as associated with prion-induced neurodegeneration, rheumatoid arthritis and temporal lobe epilepsy [8], [12], [13]. Particularly, the upregulation of miR-146 has also been demonstrated in human AD brain, suggesting that the misregulation of miR-146 could contribute to the inflammatory senile plaques pathology observed in AD [14]. In this article, we will discuss miR-146 and its potential role in AD, which may provide not only novel vision for the pathogenesis of AD, but also an interesting potential therapeutic target in AD treatment.
Section snippets
MiR-146 and its target molecules
Expression profiling has shown that miR-146 is found at high levels in trachea, lung, thymus, colon, kidney, prostate, skin, brain and most involved in immune and inflammatory response. This ubiquitous expression suggests that miR-146 may play an important physiological role. It is well established that miRNAs either block mRNA translation or reduce its stability through binding with the 3′ UTR of target molecules. The miR-146 family is comprised of two members, miR-146a and miR-146b, that are
Role of miR-146a in the pathogenesis of AD
AD and cancer have been proposed at the opposite ends of the same disease processes spectrum [24]. There are an increasing number of genetic studies and epidemiological evidences suggesting that suffering of AD is associated with a reduced risk of cancer, and conversely, a history of cancer is associated with a reduced risk of AD [25], [26]. In addition to the critical involvement of miRNA-146a in cancer initiation and progression, it has also been identified to play a crucial role in AD since
MiR-146a: Biomarker for AD?
Identifying useful biomarkers in AD is a step forward in aiding the diagnosis, especially in patients at early stage of the disease. The hunt for such markers has been a passionately pursued topic in recent years. Given that up-regulation of miR-146a is found in both AD brain and monocytes treated with LPS, it raises the concept whether measures of miR-146a derived from human blood could be used to evaluate the presence and quantify the degree of inflammation in a patient without infection.
Conclusion and perspective
In order to determine the physiological functions of miR-146a and b, it is necessary to recognize their potential targets. miR-146 inhibits a group of genes including IRAK1, TRAF6, CFH, and TSPAN12. We proposed that both miR-146a and b are involved in AD pathogenesis via suppressing the above genes and altering their downstream signaling pathways. Initially, miR-146 was identified as a negative feedback regulator in the control of Toll-like receptors and cytokine signaling, yet, the suppression
Conflict of interest
None declared.
Acknowledgements
This study was supported by the National Basic Research Development Program of China (No.2010CB945200), Shanghai Key Discipline Program (No.S30202), Shanghai Key Project of Basic Science Research (No. 09DZ1950400) and the Program for Outstanding Medical Academic Leader (No. LJ 06003).
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