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  • APP is a member of a

    2024-07-11

    APP is a member of a conserved protein family that also includes amyloid precursor-like proteins 1 and 2 (APLP1, APLP2).8, 9, 10 The proteins in this family are type I single-pass transmembrane TL32711 with receptor-like structural features but not entirely clear cellular functions.11, 12, 13, 14 These proteins have conserved structural motifs and proteolytic processing pathways and may have functional redundancy, though only APP contains the Aβ sequence associated with amyloid plaques. Two proteolytic pathways account for the majority of APP processing.15, 16 One pathway is considered non-amyloidogenic and occurs via an initial APP cleavage in the membrane-proximal region by α-secretase activity (Figure 1A). The scissile bond for this activity lies within the Aβ sequence and generates an extracellular, soluble APP fragment (sAPPα) and a membrane-bound C-terminal fragment (CTFα). CTFα is a substrate for the intramembrane protease, γ-secretase, which cleaves CTFα to yield an extracellular soluble fragment, termed P3, and the intracellular APP domain (AICD). Because α-secretase cleavage occurs within the Aβ sequence, this pathway precludes generation of the Aβ peptide. The second, amyloidogenic pathway, involves β-secretase (BACE1) cleavage of APP to liberate a soluble peptide (sAPPβ). The remaining membrane-bound C-terminal fragment (CTFβ) is subsequently cleaved by γ-secretase, generating the Aβ peptide and AICD.18, 19, 20 γ-Secretase cleaves CTFβ at multiple sites, essentially trimming the peptide into shorter, more soluble and benign forms of Aβ. While the primary species of Aβ is the 40-amino-acid form (Aβ40), inefficient cleavage can result in the release of the longer and more aggregation-prone Aβ42, which is associated with neurotoxic amyloid plaque formation.20, 22 Because of their role in the generation of Aβ, β- and γ-secretase inhibitors have been a major focus of drug development for AD, though therapeutically targeting these proteases has been challenging.23, 24 Evidence supporting a direct role for APP and Aβ in the development of AD comes from cases of autosomal-dominant forms of early-onset familial AD (eFAD/early onset AD [EOAD]), which are associated with mutations in APP or components of the γ-secretase enzyme (PSEN1 and PSEN2). These mutations alter APP cleavage resulting in an increase in total Aβ production or the ratio of Aβ42:Aβ40.7, 25, 26 Furthermore, genetic variants in proteins involved in APP cleavage can increase the risk of late-onset AD (LOAD). In addition, a mutation in APP that decreases β-secretase cleavage protects against the development of AD. A direct role for APP in AD is also suggested by the high incidence of the disease in individuals with Down syndrome/Trisomy 21 (DS/Ts21), a phenomenon that has been widely attributed to the presence of three copies of APP, which is located on chromosome 21.29, 30 APP expression has also been associated with traumatic brain injury (TBI) and has been suggested as a key factor in the development of dementia resulting from repeated injury.3, 31, 32 Although distinguished by their genetic or environmental causes and time of onset, all of these forms of AD as well as LOAD, which has risk factors but no known single genetic cause,33, 34 are considered to be the same disease with a similar sequence of symptoms and impairments. Given the overwhelming evidence for a function of APP and Aβ production in AD, strategies to downregulate APP expression or the production of Aβ are expected to have therapeutic value in disease treatment. Here, we develop a new approach for targeting APP in AD using splice-switching antisense oligonucleotides (SSOs) that specifically target and modulate APP expression in a manner that reduces Aβ production. SSOs are short, single-stranded antisense oligonucleotides (ASOs) that are designed to form Watson-Crick base pairs with a specific RNA target. SSOs can be designed to base-pair to pre-mRNA and block interactions between RNA and RNA-binding proteins involved in splicing.35, 36 In this way, the SSOs can alter splice-site recognition and modulate splicing in a directed manner. SSOs are distinct from RNase H targeting ASOs, which result in degradation of the targeted RNA. Our SSOs have 2′-O-methoxyethylribose nucleotides and a phosphorothioate-modified backbone, are water soluble, resistant to exonucleases, and highly diffusible. SSOs can be delivered to the brain by intracerebroventricular (i.c.v.) injection, thereby targeting the cells of interest and limiting dose and systemic exposure. SSOs delivered in this way have widespread distribution and cellular uptake and have a remarkably long duration of action. For these reasons, SSOs are not only useful as research tools for manipulation of gene expression, they are also a favorable therapeutic platform that has been developed for the treatment of disease.36, 39 An SSO drug (Spinraza; Biogen) has recently been approved by the Food and Drug Administration for the pediatric neurodegenerative disease spinal muscular atrophy.40, 41, 42