Abstract
One prominent and distinguishing feature of progressive, age-related neurological diseases such as Alzheimer’s disease (AD) and prion disease (PrD) is the gradual accumulation of amyloids into dense, insoluble end-stage protein aggregates. These polymorphic proteolipid lesions are known to contribute to immunogenic and inflammatory pathology in these insidious and fatal disorders of the human central nervous system (CNS). For example, the evolution of self-aggregating amyloid-beta (Aβ) peptides, such as the 42 amino acid Aβ42 peptide monomer into higher order aggregates are largely due to: (1) the inability of natural processes to clear them from the cellular environment; and/or (2) the overproduction of these amyloid monomers which rapidly mature into higher order oligomers, fibrils and insoluble, end-stage senile plaques. Cells of the CNS such as microglial (MG) cells have evolved essential homeostatic mechanisms to clear Aβ peptides to avoid their accumulation, however, when defective, these clearance mechanisms become overwhelmed and excessive deposition and aggregation of these amyloids result. This ‘Perspectives’ paper will highlight some emerging concepts on the up-regulation of an inducible microRNA-34a in AD and PrD that drives the down-regulation of the amyloid sensing- and clearance receptor protein TREM2 (the triggering receptor expressed in myeloid/microglial cells). The impairment of this inducible, miRNA-34a-regulated TREM2- and MG-cell based amyloid clearance mechanism may thereby contribute to the age-related amyloidogenesis associated with both AD and PrD.
Highlights
One prominent and distinguishing feature of progressive, age-related neurological diseases such as Alzheimer’s disease (AD) and prion disease (PrD) is the gradual accumulation of amyloids into dense, insoluble end-stage protein aggregates
Cells of the central nervous system (CNS) such as microglial (MG) cells have evolved essential homeostatic mechanisms to clear Aβ peptides to avoid their accumulation, when defective, these clearance mechanisms become overwhelmed and excessive deposition and aggregation of these amyloids result. This ‘Perspectives’ paper will highlight some emerging concepts on the up-regulation of an inducible microRNA-34a in AD and PrD that drives the down-regulation of the amyloid sensing- and clearance receptor protein TREM2
Recent miRNA array, Northern, quantitative RT-PCR, and/or RNA-sequencing-based analyses have uncovered a small group of inducible, pathogenic microRNAs significantly up-regulated in degenerating central nervous system (CNS) tissues, and these appear to be involved in the coordinate down-regulation of disease-relevant messenger RNA targets (Sethi and Lukiw, 2009; Guo et al, 2010; Lukiw et al, 2011; Yaghmoor et al, 2014; Zhao et al, 2015a,b; Bhattacharjee et al, 2016; Clement et al, 2016; University of California San Francisco [UCSF], 2016)
Summary
Recent miRNA array-, Northern-, quantitative RT-PCR, and/or RNA-sequencing-based analyses have uncovered a small group of inducible, pathogenic microRNAs (miRNAs) significantly up-regulated in degenerating central nervous system (CNS) tissues, and these appear to be involved in the coordinate down-regulation of disease-relevant messenger RNA (mRNA) targets (Sethi and Lukiw, 2009; Guo et al, 2010; Lukiw et al, 2011; Yaghmoor et al, 2014; Zhao et al, 2015a,b; Bhattacharjee et al, 2016; Clement et al, 2016; University of California San Francisco [UCSF], 2016). On the other hand significant TREM2 deficits have been reported during inflammatory neurodegeneration of the human CNS including sporadic AD and age-related macular degeneration (AMD; Zhao et al, 2013; Zhu et al, 2015; Bhattacharjee et al, 2016; Song et al, 2016) It is not clear what role TREM2 plays in amyloidogenic processes associated with prion infected human brain in Creutzfeldt-Jakob disease (CJD) or Gerstmann-StrausslerScheinker (GSS), markers of MG activation are down-regulated in prion-infected TREM2-/- mice suggesting TREM2 involvement in prion-induced MG-activation (Song et al, 2016; Ulrich and Holtzman, 2016). Using miRNA array-based analytical approaches, recent findings further indicate that miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, and miRNA-155 exhibit similar up-regulation in sporadic AD and in PrD brain (Table 1),
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