Abstract
The complete molecular mechanisms underlying the pathophysiology of Alzheimer’s disease (AD) remain to be elucidated. Recently, microRNA-455-3p has been identified as a circulating biomarker of early AD, with increased expression in post-mortem brain tissue of AD patients. MicroRNA-455-3p also directly targets and down-regulates APP, with the overexpression of miR-455-3p suppressing its toxic effects. Here, we show that miR-455-3p expression decreases with age in the brains of wild-type mice. We generated a miR-455 null mouse utilising CRISPR-Cas9 to explore its function further. Loss of miR-455 resulted in increased weight gain, potentially indicative of metabolic disturbances. Furthermore, performance on the novel object recognition task diminished significantly in miR-455 null mice (p = 0.004), indicating deficits in recognition memory. A slight increase in anxiety was also captured on the open field test. BACE1 and TAU were identified as new direct targets for miR-455-3p, with overexpression of miR-455-3p leading to a reduction in the expression of APP, BACE1 and TAU in neuroblastoma cells. In the hippocampus of miR-455 null mice at 14 months of age, the levels of protein for APP, BACE1 and TAU were all increased. Such findings reinforce the involvement of miR-455 in AD progression and demonstrate its action on cognitive performance.
Highlights
Accepted: 30 December 2021There are approximately 50 million people worldwide currently living with dementia, and this figure is predicted to rise considerably over the three decades [1,2].Alzheimer’s disease (AD) is the most common form of dementia accounting for approximately two thirds of dementia cases [3]
The miR-455 null mouse was made by the Genome Editing Unit, University of Manchester, UK
From founder mice revealed a number of deletions within the targeted pre-miR-455 locus. One of these was identified as a 35-base deletion, removing part of both miR-455-5p and miR-455-3p mature sequences, as well as the intervening hairpin sequence (Figure 1A)
Summary
Accepted: 30 December 2021There are approximately 50 million people worldwide currently living with dementia, and this figure is predicted to rise considerably over the three decades [1,2].Alzheimer’s disease (AD) is the most common form of dementia accounting for approximately two thirds of dementia cases [3]. There are approximately 50 million people worldwide currently living with dementia, and this figure is predicted to rise considerably over the three decades [1,2]. The TAU (microtubule-associated protein tau) hypothesis [9] emphasises the importance of aberrant TAU phosphorylation and subsequent NFT formation, which undermines microtubule integrity resulting in structural and transport deficits in the neurons [10,11]. Further processes such as neuroinflammation have been proposed to Published: 5 January 2022
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