MicroRNA-455-3P as a peripheral biomarker and therapeutic target for mild cognitive impairment and Alzheimer's disease

Abstract

MicroRNAs are small non-coding RNAs evolutionary conserved molecules. They regulate cellular processes, including RNA silencing, post-translational gene expression and neurodegeneration. MicroRNAs are involved with human diseases such as cancer, Alzheimer's disease (AD) and others. Interestingly, cerebrospinal fluids (CSF) and the blood of AD patients have altered expressions of many RNAs, which may serve as potential peripheral biomarkers. The intensive investigation from our lab revealed that microRNA-455-3 P (miR-455-3p) is a strong candidate as a potential biomarker and therapeutic target for AD. Several genes implicated in the pathogenesis of AD are directly targeted by miR-455-3p. Several years of our lab research revealed that miR-455-3p regulates important physiological processes associated with AD, such as the processing of the amyloid precursor protein (APP), TGF-β signaling, the regulation of oxidative stress, mitochondrial biogenesis, and synaptic damages. The expression of miR-455-3p in mild cognitive impaired subjects and AD patients pointed out its involvement in AD progression. Recently, our lab generated both transgenic and knockout mice for miR-455-3p. Interestingly miR-455-3p transgenic mice showed superior cognitive learning, improved memory and extended lifespan compared to age matched wild-type mice, whereas miR-455-3-p knockout mice showed cognitive decline and reduced lifespan. Information derived from mouse models further demonstrated the advantageous impact of miR-455-3p on dendritic growth, synaptogenesis, and mitochondrial biogenesis in preventing the onset and progression of AD. The identification of miR-455-3p as a biomarker was suggested by its presence in postmortem AD brains, B-lymphocytes, and fibroblasts. Our hypothesis that miR-455-3p could be a peripheral biomarker and therapeutic target for AD.

Keywords: Alzheimer’s disease; Amyloid precursor protein; Biomarker; Cognitive behavior; MicroRNA-455–3-p; Mitochondria; Synaptogenesis.

Figure 1:

Overview of miRNA biogenesis. miRNAs are transcribed by RNA polymerases II or III as pri-mRNA. primary miRNAs (pri-miRNAs) are recognized and excised by the microprocessor complex, composed by DiGeorge Syndrome Critical Region 8 (DGCR8) and Drosha, into a hairpin-shaped precursor-miRNAs (pre-miRNAs) via the canonical pathway in the nucleus. The pre-miRNA is exported to the cytoplasm in an Exportin 5/RanGTP-dependent manner. In the cytoplasm, dicer cleaves pre-miRNAs into tiny double-stranded miRNAs. One of the strands of the miRNA duplex is incorporated into the Argonaute (AGO) family of proteins to form a miRNA-induced silencing complex (miRISC). The miRISC complex then mediates the recognition of the target mRNA at the 3′ untranslated region, which results in mRNA instability or translational repression. The gene regulatory power of cytoplasmic miRISC typically culminates via induction of translation inhibition and mRNA poly(A) deadenylation.

Figure 2:

miR455-3p has a critical role in APP gene regulation as miR-455-3p binds to two sequence locations in the 3′ UTR of the APP gene. It ultimately decreases the level of amyloid generation and accumulation in brain.

Figure 3:

miR455-3p activates TGF beta signaling by regulating PAK2 expression,which ultimately ameliorates Alzheimer’s disease progression.

Figure 4:

Role of miR455-3p in mitochondrial biogenesis and synaptic architecture. miRNA 455-3p repress HIF1an expression and improves mitochondrial biogenesis. Our hypothesis is miRNA improved dendritic arbor and synaptic strength by positively regulating mitochondrial function and oxidative stress.

Figure 5:

Unveiling the role of different mice models of miR-455-3p in diverse physiological processes.

Figure 6:

This image illustrates the elevated expression levels of miR-455-3p in AD related specimes; serum and CSF collected from AD and MCI patients, postmortem AD brain sections, and AD cell culture models.

Figure 7:

Diagram showing the progression of the miR-455-3p detection kit development: Twenty milliliters of blood will be drawn, and it will be processed right away to separate the buffy coat and serum components. Following the isolation of total RNA, a set of procedures will be carried out, including polyadenylation and the synthesis of cDNA using primers specific to miR-455-3p. The study of fluorescence spectra will be used to confirm the correctness of miR-455-3p levels.