Impact of increased APP gene dose in Down syndrome and the Dp16 mouse model

Introduction People with Down syndrome (DS) are predisposed to Alzheimer's disease (AD). The amyloid hypothesis informs studies of AD. In AD-DS, but not sporadic AD, increased APP copy number is necessary, defining the APP gene dose hypothesis. Which amyloid precursor protein (APP) products contribute needs to be determined. Methods Brain levels of full-length protein (fl-hAPP), C-terminal fragments (hCTFs), and amyloid beta (A beta) peptides were measured in DS, AD-DS, non-demented controls (ND), and sporadic AD cases. The APP gene-dose hypothesis was evaluated in the Dp16 model. Results DS and AD-DS differed from ND and AD for all APP products. In AD-DS, A beta 42 and A beta 40 levels exceeded AD. APP products were increased in the Dp16 model; increased APP gene dose was necessary for loss of vulnerable neurons, tau pathology, and activation of astrocytes and microglia. Discussion Increases in APP products other than A beta distinguished AD-DS from AD. Deciphering AD-DS pathogenesis necessitates deciphering which APP products contribute and how.

Automated summary

DS and AD-DS show differences in all APP products compared to ND and AD. In AD-DS, levels of A beta 42 and A beta 40 exceed those in AD. Increased APP products in the Dp16 model are linked to loss of vulnerable neurons, tau pathology, and activation of astrocytes and microglia, highlighting the importance of APP gene dose in Alzheimer's disease associated with Down syndrome.