Endo-lysosomal Aß concentration and pH trigger formation of Aß oligomers that potently induce Tau missorting.
Nat Commun
; 12(1): 4634, 2021 07 30.
Article
em En
| MEDLINE
| ID: mdl-34330900
ABSTRACT
Amyloid-ß peptide (Aß) forms metastable oligomers >50 kDa, termed AßOs, that are more effective than Aß amyloid fibrils at triggering Alzheimer's disease-related processes such as synaptic dysfunction and Tau pathology, including Tau mislocalization. In neurons, Aß accumulates in endo-lysosomal vesicles at low pH. Here, we show that the rate of AßO assembly is accelerated 8,000-fold upon pH reduction from extracellular to endo-lysosomal pH, at the expense of amyloid fibril formation. The pH-induced promotion of AßO formation and the high endo-lysosomal Aß concentration together enable extensive AßO formation of Aß42 under physiological conditions. Exploiting the enhanced AßO formation of the dimeric Aß variant dimAß we furthermore demonstrate targeting of AßOs to dendritic spines, potent induction of Tau missorting, a key factor in tauopathies, and impaired neuronal activity. The results suggest that the endosomal/lysosomal system is a major site for the assembly of pathomechanistically relevant AßOs.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Endossomos
/
Peptídeos beta-Amiloides
/
Proteínas tau
/
Lisossomos
/
Neurônios
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Commun
Assunto da revista:
BIOLOGIA
/
CIENCIA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Alemanha