Work

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

Year: 2021

Type: article

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.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz.12463

Authors: 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

Institutions: University of California San Diego, Stanford Medicine, Stanford University, Banner Sun Health Research Institute, University of California, Irvine, Roswell Park Comprehensive Cancer Center

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology (medical)

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institutes of Health, National Institute on Aging, National Institute of Neurological Disorders and Stroke

Awards: Treating with Gamma-Secretase Modulators to Prevent Neurodegeneration in Mouse Models of Down Syndrome and Alzheimer Disease, Genetic Basis of Failed Cognition in Young and Aged Mouse Models of Trisomy 21, G4671396337, Multiplexed Single Nucleus RNA and ATAC-seq Sequencing and Cortical Organoids: Transformative Insights into Down Syndrome, Antisense Oligonucleotides targeting APP to prevent neurodegeneration in models of Down Syndrome and Alzheimer's disease, Arizona Alzheimer's Disease Core Center, National Brain and Tissue Resource for Parkinson's Disease and Related Disorders, Alzheimer Biomarker Consortium - Down Syndrome (ABC-DS), Arizona Alzheimer's Disease Research Center, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD), The Alzheimer's Disease Research Center at the University of California, Irvine

OpenAlex ID: W3211991404

FWCI: 5.657

Cites: 178

Cited by: 52

Related to: 10