Deficits in the miRNA-34a-regulated endogenous TREM2 phagocytosis sensor-receptor in Alzheimer's disease (AD); an update.

Abstract

One characteristic feature of Alzheimer's disease (AD) neuropathology is the progressive generation, aggregation and deposition of the 42 amino acid amyloid beta (Aβ42) peptide, and other related amyloidogenic molecules, into dense clumps of insoluble, pro-inflammatory senile plaque cores in the extracellular space of the brain. It is not generally appreciated that the Aβ42 peptide, derived via tandem beta-gamma secretase cleavage of the larger ~770 amino acid transmembrane beta-amyloid precursor protein (βAPP) is one of the “stickiest” peptides known, due in part to its high content of lipophillic and hydrophobic peptide domains (21.4% valine-isoleucine; Mager, 1998; Watson et al., 2005). Aβ42 peptide monomers have tremendously high potential for relatively rapid self-aggregation into Aβ42 peptide dimers and higher order fibrillar structures via long-range, non-covalent hydrophobic forces that over time promote β-pleated sheet conformations (Mager, 1998; Watson et al., 2005; Boutajangout and Wisniewski, 2013; Chang et al., 2013). There is abundant evidence that under normal, homeostatic conditions, Aβ42 peptide monomers and perhaps other higher order Aβ42 peptides are effectively “cleared” from the brain's extracellular medium by highly active and efficient innate-immune surveillance and phagocytic systems that limit excessive Aβ42 peptide dimerization, accumulation and further self-aggregation into pathological senile plaque lesions. Recently described, one of the key phagocytosis sensor-receptors responsible for Aβ42 peptide clearance from the human central nervous system (CNS) is very likely the triggering receptor expressed in myeloid/microglial cells 2 (TREM2) enriched in myeloid cells and microglial cells of the CNS (Benitez et al., 2013; Forabosco et al., 2013; Gonzalez Murcia et al., 2013; Guerreiro et al., 2013; Neumann and Daly, 2013; Zhao et al., 2013; Jones et al., 2014; Figure ​Figure1).1). This short paper is an update on some very recent observations on TREM2 neurobiology, on newly discovered roles for miRNA-34a-mediated signaling in human degenerative disease, including miRNA-34a-mediated effects on TREM2 expression, and how dysfunctional TREM2 signaling may contribute to amyloidogenesis in AD and in related progressive, inflammatory neurodegenerative diseases of the human CNS.