Targeting APP/AICD in Down syndrome

Down syndrome (DS), a genetic disorder caused by triplication of chromosome 21, is unavoidably associated with intellectual disability due to earlyoccurring alterations of brain development. No therapies currently exist for intellectual disability in DS. Although various triplicated genes may play a role in impairing brain development, accumulating evidence suggests that APP (amyloid precursor protein) is a particularly crucial gene. Cleavage of APP gives origin to AICD (amyloid precursor protein intracellular domain) a peptide that migrates to the nucleus and modifies the transcription of various genes, including PTCH1 (PATCHED 1) (Figure 1). PTCH1 is a receptor of SHH (Sonic Hedgehog) that binds to a second receptor, SMO (SMOOTHENED), thereby inhibiting the activity of the SHH pathway. Increased levels of AICD due to APP triplication may enhance PTCH1 transcription, which leads to excessive inhibition of the SHH pathway. Fetuses with DS exhibit increased PTCH1 levels in the VZ/SVZ [1], suggesting that early overinhibition of the SHH pathway may be a key factor underpinning the neurogenesis reduction that characterizes DS. Prompted by this line of reasoning, we exploited the Ts65Dn mouse model of DS in order to obtain evidence regarding this issue. We found that neural precursor cells (NPCs) from the SVZ of the Ts65Dn model exhibited increased levels of APP, AICD and PTCH1. Silencing of PTCH1 restored proliferation of trisomic NPCs [1], supporting the idea that SHH pathway derangement may be a central factor underlying neurogenesis reduction in DS. We then moved to in vivo experiments with the intention of pharmacologically correcting AICDmediated PTCH1 overexpression and, consequently, restoring proliferation. AICD derives from the cleavage of CTFs (carboxyterminal fragments) of APP operated by the enzyme gamma-secretase. Since reducing APP overexpression in vivo is unfeasible, we sought to reduce AICD formation by inhibiting the activity of gammasecretase. To this purpose, we used ELND006, a selective inhibitor of APP gamma-secretase created by ELAN Inc [2]. We found that Ts65Dn mice treated in the first two postnatal weeks (the period of maximum neurogenesis in the hippocampal dentate gyrus) exhibited normalized hippocampal levels of PTCH1, fully restored proliferation potency in the dentate gyrus and restored total number of granule neurons [3]. One month after treatment cessation the number of proliferating cells and total number of granule neurons were still in their restored state and the dentate gyrus-CA3 connections were functionally restored [4].