miR‐132 loss de‐represses ITPKB and aggravates amyloid and TAU pathology in Alzheimer's brain

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. image A robust miR‐132 loss has been consistently observed in AD brain. miR‐132 plays pivotal roles in maintaining the synaptic function and memory formation as well as cognitive performance. Its deficiency in AD is shown to contribute to both BACE1 and TAU pathologies. miR‐132 downregulation in the brain of an AD mouse model resulted in increased hippocampal Aβ and phosphorylated TAU levels. miR‐132 represses the inositol kinase ITPKB leading to decreased phosphorylation/activity of the ERK1/2 kinases and lowering of both TAU phosphorylation and BACE1 activity. Up‐ and downregulation of miR‐132 leads to repression or boosting of this pathway, respectively. Abrogation of the expression of the molecular players involved in this pathway was confirmed both in situ and biochemically in human AD hippocampal and cortical tissue. These findings implicate miR‐132 loss of function directly in a bimodal amplification of AD pathology and put miR‐132 forward as a putative therapeutic target in AD.