Age-Dependent Dysregulation of APP in Neuronal and Skin Cells from Fragile X Individuals

Abstract

Fragile X syndrome (FXS) is the most common form of monogenic intellectual disability and autism, caused by the absence of the functional fragile X messenger ribonucleoprotein 1 (FMRP). FXS features include increased and dysregulated protein synthesis, observed in both murine and human cells. Altered processing of the amyloid precursor protein (APP), consisting of an excess of soluble APPα (sAPPα), may contribute to this molecular phenotype in mice and human fibroblasts. Here we show an age-dependent dysregulation of APP processing in fibroblasts from FXS individuals, human neural precursor cells derived from induced pluripotent stem cells (iPSCs), and forebrain organoids. Moreover, FXS fibroblasts treated with a cell-permeable peptide that decreases the generation of sAPPα show restored levels of protein synthesis. Our findings suggest the possibility of using cell-based permeable peptides as a future therapeutic approach for FXS during a defined developmental window.

Cholesterol deficiency as a mechanism for autism: A valproic acid model

“…29,30 Derangements in amyloid processing may also be involved in ASD. [31][32][33][34] Interestingly, VPA has been found to inhibit g-secretase cleavage of amyloid precursor protein, reducing brain amyloid load and VPA hypocholesterolemic effects could be a mechanism contributing to its favorable impact on ASD via amyloid reduction. 35 This requires further exploration as most studies of this relationship have focused on cognitive impairment in older population and not on developmental effects on amyloid.…”