Mariko Sawa1, Cassia Overk1, Ann Becker1, Dominique Derse1, Ricardo Albay1, Kim Weldy1, Ahmad Salehi2, Thomas G Beach3, Eric Doran4, Elizabeth Head5, Y Eugene Yu6, William C Mobley1. 1. Department of Neurosciences, University of California San Diego, La Jolla, California, USA. 2. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA. 3. Brain and Body Donation Program, Banner Sun Health Research Institute, Sun City, Arizona, USA. 4. Department of Pediatrics, University of California, Irvine, California, USA. 5. Department of Pathology & Laboratory Medicine, University of California, Irvine, California, USA. 6. The Children's Guild Foundation Down Syndrome Research Program, Genetics and Genomics Program, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
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.
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.
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