Mariko Sawa, Cassia Overk, Ann Becker, Dominique Derse, Ricardo Albay, Kim Weldy, Ahmad Salehi, Thomas G Beach, Eric Doran, Elizabeth Head, Y Eugene Yu, William C Mobley
Alzheimer's & dementia : the journal of the Alzheimer's Association 2022 JunPeople 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. © 2021 the Alzheimer's Association.
Mariko Sawa, Cassia Overk, Ann Becker, Dominique Derse, Ricardo Albay, Kim Weldy, Ahmad Salehi, Thomas G Beach, Eric Doran, Elizabeth Head, Y Eugene Yu, William C Mobley. Impact of increased APP gene dose in Down syndrome and the Dp16 mouse model. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2022 Jun;18(6):1203-1234
PMID: 34757693
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