The microRNA-455 Null Mouse Has Memory Deficit and Increased Anxiety, Targeting Key Genes Involved in Alzheimer's Disease
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Updated: Oct 7, 2025
Stereotactic Injection of MicroRNA-expressing Lentiviruses to the Mouse Hippocampus CA1 Region and Assessment of the Behavioral Outcome
Published on: June 10, 2013
Tracey E Swingler1, Lingzi Niu1, Matthew G Pontifex2
1School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK.
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.
Insights
MicroRNA-455-3p is crucial for cognitive function and Alzheimer's disease (AD) progression. Its loss impairs memory and increases AD-related proteins, highlighting its therapeutic potential.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Alzheimer's disease (AD) pathophysiology is not fully understood.
- MicroRNA-455-3p is a potential biomarker for early AD, with elevated levels in AD patient brain tissue.
- MicroRNA-455-3p targets Amyloid Precursor Protein (APP), and its overexpression mitigates toxic effects.
Purpose of the Study:
- To investigate the role of microRNA-455 (miR-455) in cognitive function and AD pathogenesis.
- To explore the effects of miR-455 loss on behavior and molecular pathways in vivo.
Main Methods:
- Generated miR-455 knockout mice using CRISPR-Cas9.
- Assessed cognitive performance using the novel object recognition task.
- Evaluated anxiety levels via the open field test.
- Quantified protein levels of APP, BACE1, and TAU in mouse hippocampus.
- Identified BACE1 and TAU as direct targets of miR-455-3p in neuroblastoma cells.
Main Results:
- miR-455 expression decreased with age in wild-type mice.
- miR-455 null mice exhibited impaired recognition memory and increased anxiety.
- Loss of miR-455 led to elevated levels of APP, BACE1, and TAU proteins in the hippocampus.
- Overexpression of miR-455-3p reduced APP, BACE1, and TAU expression in vitro.
Conclusions:
- miR-455 plays a significant role in regulating cognitive performance.
- The miR-455 pathway is implicated in Alzheimer's disease progression.
- miR-455 influences key proteins involved in AD pathology, suggesting therapeutic relevance.
