Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease

TLDR

Macroautophagy is a lysosomal pathway that degrades organelles and long‑lived proteins and is essential for cell survival and longevity. Modulating mTOR activity to induce or inhibit macroautophagy in neuronal and nonneuronal cells alters autophagosome proliferation and β‑amyloid production. In an APP/PS1 mouse model, macroautophagy is activated early in Alzheimer’s disease before extracellular β‑amyloid deposition, and autophagic vacuoles accumulate in dystrophic dendrites, serving as a major intracellular reservoir of β‑amyloid enriched in APP, PS1, nicastrin, and γ‑secretase activity, thereby linking amyloidogenesis to cell‑survival pathways.

Abstract

Macroautophagy, which is a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. In this study, we show that neuronal macroautophagy is induced early in Alzheimer's disease (AD) and before β-amyloid (Aβ) deposits extracellularly in the presenilin (PS) 1/Aβ precursor protein (APP) mouse model of β-amyloidosis. Subsequently, autophagosomes and late autophagic vacuoles (AVs) accumulate markedly in dystrophic dendrites, implying an impaired maturation of AVs to lysosomes. Immunolabeling identifies AVs in the brain as a major reservoir of intracellular Aβ. Purified AVs contain APP and β-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent γ-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Aβ production. Our results, therefore, link β-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD.