Therapeutic Targeting of Casein Kinase 1δ/ε in an Alzheimer's Disease Mouse Model

J Proteome Res. 2019 Sep 6;18(9):3383-3393. doi: 10.1021/acs.jproteome.9b00312. Epub 2019 Aug 6.

Abstract

Sleep disturbances and memory impairment are common symptoms of Alzheimer's disease (AD). Given that the circadian clock regulates sleep, hippocampal function, and neurodegeneration, it represents a therapeutic target against AD. Casein kinase 1δ/ε (CK1δ/ε) are clock regulators and overexpressed in AD brains, making them viable targets to improve sleep and cognition. In this study, we evaluated the therapeutic potential of a small molecule CK1δ/ε inhibitor (PF-670462) in a triple transgenic mouse model of AD (3xTg-AD). Mass spectrometry-based proteomic analyses revealed that PF-670462 administration in 3xTg-AD mice reversed hippocampal proteomic alterations in several AD-related and clock-regulated pathways, including synaptic plasticity and amyloid precursor protein processing. Furthermore, PF-670462 administration rescued working memory deficits and normalized behavioral circadian rhythm disturbances in 3xTg-AD mice. Our study provides in vivo proof of concept for CK1δ/ε inhibition against AD-associated hippocampal proteomic changes, memory impairment, and circadian disturbances.

Keywords: 3xTg-AD; Alzheimer’s disease; casein kinase 1; circadian; hippocampus; mass spectrometry; memory; proteome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology
  • Alzheimer Disease / therapy*
  • Animals
  • Casein Kinase Idelta / antagonists & inhibitors
  • Casein Kinase Idelta / genetics*
  • Casein Kinase Iepsilon / antagonists & inhibitors
  • Casein Kinase Iepsilon / genetics*
  • Circadian Clocks / genetics
  • Disease Models, Animal
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Memory Disorders / complications
  • Memory Disorders / genetics
  • Memory Disorders / pathology
  • Memory Disorders / therapy*
  • Mice
  • Mice, Transgenic
  • Nerve Degeneration / genetics
  • Neuronal Plasticity / drug effects
  • Proteomics / methods
  • Pyrimidines / pharmacology
  • Sleep Wake Disorders / complications
  • Sleep Wake Disorders / genetics
  • Sleep Wake Disorders / pathology
  • Sleep Wake Disorders / therapy*

Substances

  • Pyrimidines
  • PF-670462
  • Casein Kinase Idelta
  • Casein Kinase Iepsilon