Lysosomal dysfunction in down syndrome is app-dependent and mediated by APP-βCTF (c99)

Ying Jiang, Yutaka Sato, Eunju Im, Martin Berg, Matteo Bordi, Sandipkumar Darji, Asok Kumar, Panaiyur S. Mohan, Urmi Bandyopadhyay, Antonio Diaz, Ana Maria Cuervo, Ralph A. Nixon

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Lysosomal failure underlies pathogenesis of numerous congenital neurodegenerative disorders and is an early and progressive feature of Alzheimer’s disease (AD) pathogenesis. Here, we report that lysosomal dysfunction in Down ayndrome (trisomy 21), a neurodevelopmental disorder and form of early onset AD, requires the extra gene copy of amyloid precursor protein (APP) and is specifically mediated by the β cleaved carboxy terminal fragment of APP (APP-βCTF, C99). In primary fibroblasts from individuals with DS, lysosomal degradation of autophagic and endocytic substrates is selectively impaired, causing them to accumulate in enlarged autolysosomes/lysosomes. Direct measurements of lysosomal pH uncovered a significant elevation (0.6 units) as a basis for slowed LC3 turnover and the inactivation of cathepsin D and other lysosomal hydrolases known to be unstable or less active when lysosomal pH is persistently elevated. Normalizing lysosome pH by delivering acidic nanoparticles to lysosomes ameliorated lysosomal deficits, whereas RNA sequencing analysis excluded a transcriptional contribution to hydrolase declines. Cortical neurons cultured from the Ts2 mouse model of DS exhibited lysosomal deficits similar to those in DS cells. Lowering APP expression with siRNA or BACE1 inhibition reversed cathepsin deficits in both fibroblasts and neurons. Deleting one Bace1 allele from adult Ts2 mice had similar rescue effects in vivo. The modest elevation of endogenous APP-βCTF needed to disrupt lysosomal function inDSis relevant to sporadicADwhere APP-βCTF, but not APP, is also elevated. Our results extend evidence that impaired lysosomal acidification drives progressive lysosomal failure in multiple forms of AD.

Original languageEnglish (US)
Pages (from-to)5255-5268
Number of pages14
JournalJournal of Neuroscience
Volume39
Issue number27
DOIs
StatePublished - Jul 3 2019

Keywords

  • AD
  • APP-βCTF
  • Cathepsin D
  • Down syndrome
  • Lysosomal pH
  • Lysosome

ASJC Scopus subject areas

  • Neuroscience(all)

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    Jiang, Y., Sato, Y., Im, E., Berg, M., Bordi, M., Darji, S., Kumar, A., Mohan, P. S., Bandyopadhyay, U., Diaz, A., Cuervo, A. M., & Nixon, R. A. (2019). Lysosomal dysfunction in down syndrome is app-dependent and mediated by APP-βCTF (c99). Journal of Neuroscience, 39(27), 5255-5268. https://doi.org/10.1523/JNEUROSCI.0578-19.2019