Amyloid precursor protein mRNA (APP mRNA)

Amyloid precursor protein (APP) mRNA is the transcript responsible for the synthesis of the amyloid precursor protein, a type I transmembrane protein expressed at high levels in the central nervous system. The processing of the APP protein by beta- and gamma-secretases leads to the generation of amyloid-beta (Aβ) peptides, which aggregate into the neurotoxic plaques characteristic of Alzheimer's disease (Citations: UniProt: P05067, PubMed: 27629444). Targeting the mRNA directly offers a strategy to reduce the production of all APP isoforms and their subsequent cleavage products, potentially slowing disease progression more effectively than targeting individual Aβ species. Therapeutic approaches targeting APP mRNA include small molecules that inhibit translation by binding to regulatory elements in the 5' UTR, as well as RNA-targeted therapies like antisense oligonucleotides (ASOs) and siRNAs that promote mRNA degradation. By lowering the overall expression of APP, these drugs aim to decrease the burden of Aβ and other neurotoxic fragments like C99 and sAPPβ (Citations: PubMed: 35143256). Clinical development in this area is focused on treating early-onset Alzheimer's disease and Down syndrome-related dementia, where APP overexpression is a primary driver of pathology.

Other names

Amyloid beta precursor protein mRNAAPP transcriptA4 amyloid protein mRNAPreprotein amyloid mRNA

Drugs targeting APP mRNA typically function through translation inhibition or targeted degradation. Small molecules like buntanetap bind to the iron-responsive element (IRE) in the 5' untranslated region (UTR) of the mRNA to block ribosomal recruitment and protein translation (Citations: PubMed: 33571004, NIH: PMC7875118). Oligonucleotide-based therapies, such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), bind to the mRNA via Watson-Crick base pairing to induce RNase H-mediated cleavage or RNA-induced silencing complex (RISC) mediated degradation, respectively, thereby reducing the total pool of APP protein available for amyloidogenic processing (Citations: Alnylam Pharmaceuticals, Ionis Pharmaceuticals).