Sawa, MarikoOverk, CassiaBecker, AnnDerse, DominiqueAlbay, RicardoWeldy, KimSalehi, AhmadBeach, Thomas GDoran, EricHead, ElizabethYu, Y EugeneMobley, William C
Those with Down syndrome (DS) are predisposed to developing Alzheimer’s disease (AD) and often experience early onset AD. This study explores the amyloid hypothesis which posits that the accumulation of a molecule called oligomeric or fibrillar amyloid β (Aβ) peptide is the primary cause of AD. Specifically, researchers look at a protein called the amyloid precursor protein (APP) that contributes to AD in those with DS.
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. Brain levels of full-length protein (fl-hAPP), C-terminal fragments (hCTFs), and amyloid beta (Aβ) 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. DS and AD-DS differed from ND and AD for all APP products. In AD-DS, Aβ42 and Aβ40 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. Increases in APP products other than Aβ distinguished AD-DS from AD. Deciphering AD-DS pathogenesis necessitates deciphering which APP products contribute and how.