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  • Despite clear evidence of a causative role for A in

    2023-05-26

    Despite clear evidence of a causative role for Aβ in AD, Aβ-mediated toxicity alone is insufficient to explain all facets of fully manifested AD. Indeed, a recent report found that two familial AD mutations in PSEN1, PSEN-L435F and PSEN-C410Y, resulted in a dysfunctional protein that does not cleave APP, suggesting a possible Aβ-independent mechanism of AD. However, follow-up experiments by Veugelen et al., demonstrated proteolytic activity from proteins with these mutations. Moreover, in these mutants, the loss of processive carboxypeptidase activity resulted in longer Aβ peptides, which are highly competent for seeding amyloid aggregates, consistent with in vivo observations of AD-related presenilin activity. Antisense strategies targeting APP expression in vivo have been previously explored.63, 64, 65 For example, Kumar et al. reported that administration of an APP-targeted ASO to mice lowers APP protein and Aβ peptide levels and ameliorates physiological and behavioral pathology in animal models of aging and AD. However, it is important to note that ASOs used in previous studies are comprised, at least in part, of deoxynucleotides, which, upon Ticarcillin sodium sale pairing to RNA create a substrate for RNase H, resulting in cleavage of the duplexed RNA and a predicted overall decrease in APP protein levels. Our use of SSOs to induce APP alternative splicing and production of an mRNA that encodes an APP protein that cannot produce Aβ is a novel approach for downregulating APP and APP proteolysis that does not alter total APP protein levels. The SSOs that we have designed induce skipping of the APP exon that encodes the cleavage sites necessary to generate toxic Aβ species. However, the majority of APP is intact in the APPΔex17 protein. Although the function of APP is not entirely clear, there is evidence to suggest that it acts as a receptor, given its similarities in structure to other type I transmembrane receptors as well as the discovery of receptor-like proteins that bind APP.8, 9, 67 APP has also been implicated in cell adhesion. Importantly, our antisense approach is aimed at downregulating pathological overexpression of APP in order to normalize APP levels and is not expected to produce a complete switch to the APPΔex17 protein isoform. Thus, there will be full-length APP available to perform important functions of the intact protein after SSO treatment. The homologs of APP, APLP1 and APLP2, will also likely offer some functional redundancy. One important factor in our approach is that the APPΔex17 protein does not appear to result in a gain of toxic function. We did not observe overt signs of toxicity in the SSO-treated mice expressing APPΔex17 (Figure S2). In addition, we demonstrate that the APPΔex17 isoform is secreted into the culture media (Figure 1) and thus may preserve some of the functions of secreted APP, which have been reported to be neuroprotective and involved in the enhancement of long-term potentiation and memory. More detailed studies investigating long-term effects of APPΔex17 expression in vivo will be needed to more definitively assess any potential toxic or beneficial affects associated with expression of the novel APP isoform. AD treatments have struggled in clinical trials with few drugs advancing toward the market in the past 30 years. There are currently six FDA approved drugs for AD, though these treatments only temporarily improve symptoms and do not target the underlying causes of the disease that lead to fatal neurodegeneration. There are a number of anti-amyloid antibodies in clinical development that have shown promise in clinical trials, further demonstrating the therapeutic value of targeting Aβ.1, 70 As an alternative to antibody and small-molecule therapeutic development, SSOs are a good platform for the treatment of neurological disorders, offering safe, long-lasting alterations in the gene expression following direct administration to the central nervous system.36, 38, 66 Indeed, an SSO has recently been approved for the treatment of the fatal pediatric neurodegenerative disease spinal muscular atrophy (SMA).40, 71 The study presented here provides the basis for a therapeutic strategy for reduction of Aβ by modulation of APP pre-mRNA splicing to produce a cleavage-deficient protein isoform, offering an innovative approach for the treatment of AD.