Protective Mechanisms of MicroRNA-455-3p Against the Neurodegeneration in Alzheimer’s Disease
Introduction. Alzheimer’s Disease (AD) is the most common cause of dementia in the world and involves the progressive loss of episodic memory and cognitive function with later deficiencies in language. This condition is often accompanied by behavioral disorders including apathy and depression.1 Pathogenesis is still highly debated, making it even harder to find to identify both a biomarker and cure for AD. MicroRNA-455-3p is a potential biomarker and therapeutic agent. It is found to be elevated in AD patients and to have neuroprotective mechanisms against the pathogenesis of AD.2 Methods. Mice w ere either transfected with miR-455-3p or had their genes for the microRNA knocked out. These studies observed differences in the transgenic, knockout, and wild-type mice. These differences included survival and behavior.1,3,4 Levels of APP (amyloid precursor protein), mitochondrial biogenesis and synaptic proteins were also recorded.1,3 Imaging of hippocampal and cortical sections of 12-month-old mice was performed to observe synapses.1 DNA samples were also gathered from AD patients at the FRONTIERS project based at TTUHSC.2 Results. A significant increase of miR-455-3p can be seen in the post-mortem brains, specifically Brodmann’s area 10, of AD patients.4 The KO mice models had the worst survival rate and presented with the highest amount of APP.3 The accumulation of APP is known to promote the levels of neurofibrillary tangles and this ultimately leads to neurotoxicity. KO mice also displayed lower levels cognitive function in which they showed lower levels of novel object recognition and higher levels of anxiety.4 RT-PCR showed decreased levels of mitochondrial biogenesis proteins and synaptic proteins.3 MiR-455-3p directly upregulates PGC1a which leads to increases in NFR-1 and NRF-2, and these two targets ultimately increase TFAM, a key enhancer protein in mitochondrial biogenesis.1,3 RT-PCR also showed lower levels of synaptic proteins SNAP25, MAP2, and PSD95 in KO mice.1 This resulted in a decrease in all neuronal spine density, length, and synapses in KO mice.1 Conclusions. The high level of miR-455-3p is transcribed in response to the neurodegeneration involved in the pathogenesis of AD and this makes it a potential biomarker for AD.4 MiR-455-3p was found to be directly involved with the production of mitochondrial biogenesis proteins and it was also found to be involved with more synaptic proteins and less APP, although these relationships are less understood.1,3 The effect of these protein levels can be seen in the transgenic mice model in which the transgenic mice lived longer, performed better on behavioral tests, and showed healthier neuronal synapses.1,3,4 Therefore, miR-455-3p could potentially be a therapeutic agent for AD as well. However, route of administration and specificity of miR use is still a barrier and must be investigated more deeply before its use as a therapeutic agent.
- Kumar S, Morton H, Sawant N, Orlov E, Bunquin LE, Pradeepkiran JA, Alvir R, Reddy PH. MicroRNA-455-3p improves synaptic, cognitive functions and extends lifespan: Relevance to Alzheimer’s disease. Redox Biol. 2021 Nov 9;48:102182. doi: 10.1016/j.redox.2021.102182. Epub ahead of print. PMID: 34781166; PMCID: PMC8604688.
- Kumar S, Vijayan M, Reddy PH. MicroRNA-455-3p as a potential peripheral biomarker for Alzheimer’s disease. Hum Mol Genet. 2017 Oct 1;26(19):3808-3822. doi: 10.1093/hmg/ddx267. PMID: 28934394; PMCID: PMC6075184.
- Kumar S, Reddy AP, Yin X, Reddy PH. Novel MicroRNA-455-3p and its protective effects against abnormal APP processing and amyloid beta toxicity in Alzheimer’s disease. Biochim Biophys Acta Mol Basis Dis. 2019 Sep 1;1865(9):2428-2440. doi: 10.1016/j.bbadis.2019.06.006. Epub 2019 Jun 8. PMID: 31181293; PMCID: PMC6688505.
- Swingler TE, Niu L, Pontifex MG, Vauzour D, Clark IM. The microRNA-455 Null Mouse Has Memory Deficit and Increased Anxiety, Targeting Key Genes Involved in Alzheimer’s Disease. Int J Mol Sci. 2022 Jan 5;23(1):554. doi: 10.3390/ijms23010554. PMID: 35008980; PMCID: PMC8745123.
- Abuelezz NZ, Nasr FE, AbdulKader MA, Bassiouny AR, Zaky A. MicroRNAs as Potential Orchestrators of Alzheimer’s Disease-Related Pathologies: Insights on Current Status and Future Possibilities. Front Aging Neurosci. 2021 Oct 12;13:743573. doi: 10.3389/fnagi.2021.743573. PMID: 34712129; PMCID: PMC8546247.
- Gowda P, Reddy PH, Kumar S. Deregulated mitochondrial microRNAs in Alzheimer’s disease: Focus on synapse and mitochondria. Ageing Res Rev. 2022 Jan;73:101529. doi: 10.1016/j.arr.2021.101529. Epub 2021 Nov 20. PMID: 34813976; PMCID: PMC8692431.
- Kumar S, Reddy PH. MicroRNA-455-3p as a Potential Biomarker for Alzheimer’s Disease: An Update. Front Aging Neurosci. 2018 Feb 23;10:41. doi: 10.3389/fnagi.2018.00041. PMID: 29527164; PMCID: PMC5829054.
- Silva MVF, Loures CMG, Alves LCV, de Souza LC, Borges KBG, Carvalho MDG. Alzheimer’s disease: risk factors and potentially protective measures. J Biomed Sci. 2019 May 9;26(1):33. doi: 10.1186/s12929-019-0524-y. PMID: 31072403; PMCID: PMC6507104.