1-L Transcription in Alzheimer's Disease

Abstract

Alzheimer's disease is a very complex disease and better explanations and models are needed to understand how neurons are affected and microglia are activated. A new model of Alzheimer's disease is presented here, the β-amyloid peptide is considered an important RNA recognition/binding peptide. 1-L transcription revealed compatible sequences with AAUAAA (PAS signal) and UUUC (class III ARE rich in U) in the Aβ peptide, supporting the peptide-RNA regulatory model. When a hypothetical model of fibril selection with the prionic character of amyloid assemblies is added to the peptide-RNA regulatory model, the downregulation of the PI3K-Akt pathway and the upregulation of the PLC-IP3 pathway are well explained. The model explains why neurons are less protected from inflammation and why microglia are activated; why mitochondria are destabilized; why the autophagic flux is destabilized; and why the post-transcriptional attenuation of the axonal signal "noise" is interrupted. For example, the model suggests that Aβ peptide may post-transcriptionally control ELAVL2 (ELAV-like RNA binding protein 2) and DCP2 (decapping mRNA protein 2), which are known to regulate RNA processing, transport, and stability.

Keywords: Alzheimer’s disease; bioinformatics method; identified genes; protein–RNA recognition code; β-amyloid peptide.

Figure 1

Graphic representation of cells in the brain. Nerve mRNAs and RBPs are transferred from the nucleus via the axon (exosomal pathway, anterograde), and glial mRNAs and RBPs are transferred from the extracellular space to the nucleus (endosomal pathway, retrograde). Dysregulation of APP/Aβ, TAU, and APOE functions are the basic three characteristics of AD. Due to the dysregulation of these three genes/proteins, disruption of axonal transport can be observed in AD.

Figure 2

1-L code and 1-L RBP HUR transcription. HUR is a key regulator of cellular mRNAs containing adenylate/uridylate-rich (ARE) elements, for example, it regulates the stability of FOS mRNA. It has three RNA recognition motifs (RRM), the first is the most conserved and can be accurately transcribed into ARE and PAS sequences by 1-L transcription. The structure of RRM1-RRM2 (4ed5) shows that the sequence 21NLIVN is involved in ARE recognition, but the uncrystallized disordered N-terminus may also be involved in recognition, based on the obtained 1-L compatibility between the HUR N-terminus and the c-FOS 3′UTR.

Figure 3

Two different pathways of APP processing in PM, and healthy oligomerization of Aβ peptide to elicit immune responses versus toxic prion oligomerization. The 1-L transcription of the Aβ peptide identifies the PAS sequence and the TTTC sequence (U-rich ARE class III). Genes identified by 1-L transcription, green highlights show alignments with complement sequence (post-transcriptionally repressed), yellow highlights show alignments with reverse complement sequence (post-transcriptionally promoted).

Figure 4

Identified genes/proteins with functions in the plasma membrane and at the PM-cytosol interface. The description of genes/proteins is given in the text from the top left corner down. Green highlights show alignments with the complement sequence (post-transcriptionally repressed), yellow highlights show alignments with the reverse complement sequence (post-transcriptionally promoted).

Figure 5

Identified genes/proteins with functions in membrane organelles, mitochondria, and nucleus. The descriptions of genes/proteins are given in the text, from endosomes to nucleus, from left to right. Green highlights show alignments with the complement sequence (post-transcriptionally repressed), yellow highlights show alignments with the reverse complement sequence (post-transcriptionally promoted).

Figure 6

The situation when the prion-like oligomerization consumes the Aβ signal peptide. Green highlights show the alignments with the reverse complement sequence (post-transcriptionally not promoted), yellow highlights show the alignments with the complement sequence (post-transcriptionally not repressed).