TFEB in Alzheimer's disease: From molecular mechanisms to therapeutic implications

Neurobiol Dis. 2022 Oct 15;173:105855. doi: 10.1016/j.nbd.2022.105855. Epub 2022 Aug 27.

Abstract

Alzheimer's disease (AD), an age-dependent neurodegenerative disorder, is the most prevalent neurodegenerative disease worldwide. The primary pathological hallmarks of AD are the deposition of β-amyloid plaques and neurofibrillary tangles. Autophagy, a pathway of clearing damaged organelles, macromolecular aggregates, and long-lived proteins via lysosomal degradation, has emerged as critical for proteostasis in the central nervous system (CNS). Studies have demonstrated that defective autophagy is strongly implicated in AD pathogenesis. Transcription factor EB (TFEB), a master transcriptional regulator of autophagy, enhances the expression of related genes that control autophagosome formation, lysosome function, and autophagic flux. The study of TFEB has greatly increased over the last decade, and the dysfunction of TFEB has been reported to be strongly associated with the pathogenesis of many neurodegenerative disorders, including AD. Here, we delineate the basic understanding of TFEB dysregulation involved in AD pathogenesis, highlighting the existing work that has been conducted on TFEB-mediated autophagy in neurons and other nonneuronal cells in the CNS. Additionally, we summarize the small molecule compounds that target TFEB-regulated autophagy involved in AD therapy. Our review may yield new insights into therapeutic approaches by targeting TFEB and provide a broadly applicable basis for the clinical treatment of AD.

Keywords: Alzheimer's disease; Autophagy; Aβ plaque; Lysosome; Tau phosphorylation; Transcription factor EB.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / genetics
  • Amyloid beta-Peptides / metabolism
  • Autophagy / physiology
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Humans
  • Lysosomes / metabolism
  • Neurodegenerative Diseases* / metabolism
  • Plaque, Amyloid / metabolism

Substances

  • Amyloid beta-Peptides
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • TFEB protein, human