Abstract
microRNA‐132 (miR‐132) is involved in prosurvival, anti‐inflammatory and memory‐promoting functions in the nervous system and has been found consistently downregulated in Alzheimer's disease (AD). Whether and how miR‐132 deficiency impacts AD pathology remains, however, unaddressed. We show here that miR‐132 loss exacerbates both amyloid and TAU pathology via inositol 1,4,5‐trisphosphate 3‐kinase B (ITPKB) upregulation in an AD mouse model. This leads to increased ERK1/2 and BACE1 activity and elevated TAU phosphorylation. We confirm downregulation of miR‐132 and upregulation of ITPKB in three distinct human AD patient cohorts, indicating the pathological relevance of this pathway in AD.
Highlights
The pathogenic process in Alzheimer’s disease (AD) involves a long cellular phase during which intricate feedback and feed-forward cascades between distinct cell types affect the homeostasis of the brain
Even if the disruption of miRNA expression is part of the general pathogenic process induced by accumulating toxic cues, it remains important to investigate whether loss or gain of function of particular miRNAs has a specific functional impact on AD pathology. miRNAs that are systematically and early downregulated in the disease course are of particular interest in that regard
We demonstrate here that downregulation of miR-132 aggravates both amyloid and TAU pathology in AD mice and that it regulates the expression of inositol 1,4,5-trisphosphate 3-kinase B (ITPKB), a regulator of BACE1 activity and TAU phosphorylation (Stygelbout et al, 2014)
Summary
The pathogenic process in Alzheimer’s disease (AD) involves a long cellular phase during which intricate feedback and feed-forward cascades between distinct cell types affect the homeostasis of the brain. MiR-132 deficiency in AD brain might have additional neurotoxic effects as miR-132 is involved in neuronal plasticity and synaptic function (Edbauer et al, 2010; Bicker et al, 2014; Salta et al, 2014), it has been implicated in neuroinflammation and the regulation of acetylcholinesterase expression (Shaked et al, 2009), while activity-induced CREB-dependent miR-132 transcription contributes to memory formation and cognition (Hansen et al, 2013). Overall these observations suggest that loss of miR-132 could play a pivotal role in several aspects of AD. To date, little hard data are available providing factual support to the hypothesis that miR-132 is part of the disease process
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