miRNA Alterations Elicit Pathways Involved in Memory Decline and Synaptic Function in the Hippocampus of Aged Tg4-42 Mice

Abstract

The transcriptome of non-coding RNA (ncRNA) species is increasingly focused in Alzheimer's disease (AD) research. NcRNAs comprise, among others, transfer RNAs, long non-coding RNAs and microRNAs (miRs), each with their own specific biological function. We used smallRNASeq to assess miR expression in the hippocampus of young (3 month old) and aged (8 month old) Tg4-42 mice, a model system for sporadic AD, as well as age-matched wildtype controls. Tg4-42 mice express N-truncated Aβ 4-42 , develop age-related neuron loss, reduced neurogenesis and behavioral deficits. Our results do not only confirm known miR-AD associations in Tg4-42 mice, but more importantly pinpoint 22 additional miRs associated to the disease. Twenty-five miRs were differentially expressed in both aged Tg4-42 and aged wildtype mice while eight miRs were differentially expressed only in aged wildtype mice, and 33 only in aged Tg4-42 mice. No significant alteration in the miRNome was detected in young mice, which indicates that the changes observed in aged mice are downstream effects of Aβ-induced pathology in the Tg4-42 mouse model for AD. Targets of those miRs were predicted using miRWalk. For miRs that were differentially expressed only in the Tg4-42 model, 128 targets could be identified, whereas 18 genes were targeted by miRs only differentially expressed in wildtype mice and 85 genes were targeted by miRs differentially expressed in both mouse models. Genes targeted by differentially expressed miRs in the Tg4-42 model were enriched for negative regulation of longterm synaptic potentiation, learning or memory, regulation of trans-synaptic signaling and modulation of chemical synaptic transmission obtained. This untargeted miR sequencing approach supports previous reports on the Tg4-42 mice as a valuable model for AD. Furthermore, it revealed miRs involved in AD, which can serve as biomarkers or therapeutic targets.

N-Truncated Aβ Starting at Position Four—Biochemical Features, Preclinical Models, and Potential as Drug Target in Alzheimer’s Disease

“…A significant number of mRNAs were associated with memory deficits and neuron loss, which points to common disease pathways in both AD models (Bouter et al, 2014 ). Moreover, small RNA sequencing of the microRNAome in the hippocampus of Tg4–42 mice revealed microRNAs involved in learning, memory function, and synaptic signaling (Bouter et al, 2020 ). Metabolic changes of the glutamate/4-aminobutyrate-glutamine axis correlated with neurological deficits, neurodegeneration, and elevated CSF levels of neurofilament light chain in aged Tg4–42 mice (Hinteregger et al, 2021 ).…”

Potential Targets and Pharmacological Effects of Wuling Capsule on Alzheimer’s Disease: A Network Pharmacology-based Analysis

“…Studies have shown that inhibition of Aβ-induced pathological mechanisms can attenuate cognitive impairment by targeting genes for trans-synaptic signaling. 41 However, the above is only an analysis based on the database. Next, pharmacological experiments are needed to verify the mechanism of the Wuling capsule in the treatment of AD.…”

Fission Impossible: Stabilized miRNA-Based Analogs in Neurodegenerative Disease

“…The significant heterogeneity in the presentation of AD is based in part on individual variation in genetics, genetic and familial history, the abundance and speciation of different SP and NFT isoforms in anatomical regions of the brain involved with cognition and memory, the Braak stage of the disease, the environment, diet and lifestyle, inter-current illness, multiple parameters associated with gender and aging and other factors associated with the intrinsic complexity of the disease itself (DeTure and Dickson, 2019 ; Habes et al, 2020 ). Since the first reported alterations of miRNA abundance, speciation and complexity in the affected regions of AD brain much research attention has been placed on: (i) the abundance, speciation, stability and lability of brain-enriched miRNAs; and (ii) how miRNA patterns are altered during the initiation and propagation of the neurodegenerative disease process as is observed both in affected AD tissues and in transgenic murine research models for AD (TgAD; Lukiw, 2007 ; Sobue, 2013 ; Bouter et al, 2020 ; Zhao et al, 2020 ; Lauretti et al, 2021 ; Pogue and Lukiw, 2021 ; Tasker et al, 2021 ).…”