Mechanisms by which autophagy regulates memory capacity in ageing

Aging Cell. 2020 Sep;19(9):e13189. doi: 10.1111/acel.13189. Epub 2020 Jul 30.

Abstract

Autophagy agonists have been proposed to slow down neurodegeneration. Spermidine, a polyamine that acts as an autophagy agonist, is currently under clinical trial for the treatment of age-related memory decline. How Spermidine and other autophagy agonists regulate memory and synaptic plasticity is under investigation. We set up a novel mouse model of mild cognitive impairment (MCI), in which middle-aged (12-month-old) mice exhibit impaired memory capacity, lysosomes engulfed with amyloid fibrils (β-amyloid and α-synuclein) and impaired task-induced GluA1 hippocampal post-translation modifications. Subchronic treatment with Spermidine as well as the autophagy agonist TAT-Beclin 1 rescued memory capacity and GluA1 post-translational modifications by favouring the autophagy/lysosomal-mediated degradation of amyloid fibrils. These findings provide new mechanistic evidence on the therapeutic relevance of autophagy enhancers which, by improving the degradation of misfolded proteins, slow down age-related memory decline.

Keywords: GluA1; Spermidine; ageing; alpha-synuclein; amyloid fibrils; autophagy; mild cognitive impairment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Animals
  • Autophagy / genetics*
  • Cognitive Dysfunction / genetics*
  • Disease Models, Animal
  • Memory / drug effects*
  • Mice