Dataset Information
Impact of increased APP gene dose in Down syndrome and the Dp16 mouse model.
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ABSTRACT: 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 (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.Results
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.Discussion
Increases in APP products other than Aβ distinguished AD-DS from AD. Deciphering AD-DS pathogenesis necessitates deciphering which APP products contribute and how.
SUBMITTER: Sawa M
PROVIDER: S-EPMC9085977 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
Publications
Impact of increased APP gene dose in Down syndrome and the Dp16 mouse model.
Alzheimer's & dementia : the journal of the Alzheimer's Association 20211110 6
<h4>Introduction</h4>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.<h4>Methods</h4>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 c ...[more]