Presenilins as drug targets for Alzheimer’s disease—recent insights from cell biology and electrophysiology as novel opportunities in drug development

R. Scott Duncan, Bob Song, Peter Koulen

Research output: Contribution to journalReview articlepeer-review

18 Scopus citations

Abstract

A major cause underlying familial Alzheimer’s disease (AD) are mutations in presenilin proteins, presenilin 1 (PS1) and presenilin 2 (PS2). Presenilins are components of the γ-secretase complex which, when mutated, can affect amyloid precursor protein (APP) processing to toxic forms of amyloid beta (Aβ). Consequently, presenilins have been the target of numerous and varied research efforts to develop therapeutic strategies for AD. The presenilin 1 gene harbors the largest number of AD-causing mutations resulting in the late onset familial form of AD. As a result, the majority of efforts for drug development focused on PS1 and Aβ. Soon after the discovery of the major involvement of PS1 and PS2 in γ-secretase activity, it became clear that neuronal signaling, particularly calcium ion (Ca2+) signaling, is regulated by presenilins and impacted by mutations in presenilin genes. Intracellular Ca2+ signaling not only controls the activity of neurons, but also gene expression patterns, structural functionality of the cytoskeleton, synaptic connectivity and viability. Here, we will briefly review the role of presenilins in γ-secretase activity, then focus on the regulation of Ca2+ signaling, oxidative stress, and cellular viability by presenilins within the context of AD and discuss the relevance of presenilins in AD drug development efforts.

Original languageEnglish (US)
Article number1621
JournalInternational journal of molecular sciences
Volume19
Issue number6
DOIs
StatePublished - Jun 2018

Keywords

  • Amyloid beta
  • Calcium signaling
  • Drug target discovery
  • Endoplasmic reticulum
  • Inositol 1,4,5-trisphosphate receptor
  • Ion channel
  • Oxidative stress
  • Ryanodine receptor
  • Therapy
  • γ-secretase

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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