Phloroglucinol Attenuates the Cognitive Deficits of the 5XFAD Mouse Model of Alzheimer's Disease

PLoS One. 2015 Aug 18;10(8):e0135686. doi: 10.1371/journal.pone.0135686. eCollection 2015.

Abstract

Alzheimer's disease (AD) is the most common form of dementia among the elderly. Neuritic plaques whose primary component is amyloid beta peptide (Aβ) and neurofibrillary tangles which are composed of hyperphosphorylated tau, are known to be the neuropathological hallmarks of AD. In addition, impaired synaptic plasticity in neuronal networks is thought to be important mechanism underlying for the cognitive deficits observed in AD. Although various causative factors, including excitotoxicity, mitochondrial dysregulation and oxidative damage caused by Aβ, are involved in early onset of AD, fundamental therapeutics that can modify the progression of this disease are not currently available. In the present study, we investigated whether phloroglucinol (1, 3, 5-trihydroxybenzene), a component of phlorotannins, which are plentiful in Ecklonia cava, a marine brown alga species, displays therapeutic activities in AD. We found that phloroglucinol attenuates the increase in reactive oxygen species (ROS) accumulation induced by oligomeric Aβ1-42 (Aβ1-42) treatment in HT-22, hippocampal cell line. In addition, phloroglucinol was shown to ameliorate the reduction in dendritic spine density induced by Aβ1-42 treatment in rat primary hippocampal neuron cultures. We also found that the administration of phloroglucinol to the hippocampal region attenuated the impairments in cognitive dysfunction observed in 22-week-old 5XFAD (Tg6799) mice, which are used as an AD animal model. These results indicate that phloroglucinol displays therapeutic potential for AD by reducing the cellular ROS levels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / chemically induced
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / physiopathology*
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / toxicity
  • Animals
  • Cell Line
  • Cognition / drug effects*
  • Dendritic Spines / drug effects
  • Disease Models, Animal
  • Disks Large Homolog 4 Protein
  • Female
  • Guanylate Kinases / metabolism
  • Hippocampus / cytology
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Humans
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • Maze Learning / drug effects
  • Membrane Proteins / metabolism
  • Mice
  • Peptide Fragments / chemistry
  • Peptide Fragments / toxicity
  • Phloroglucinol / pharmacology*
  • Phloroglucinol / therapeutic use
  • Pregnancy
  • Protein Multimerization / drug effects
  • Protein Structure, Secondary
  • Rats
  • Reactive Oxygen Species / metabolism
  • Synapses / drug effects
  • Synaptophysin / metabolism

Substances

  • Amyloid beta-Peptides
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Membrane Proteins
  • Peptide Fragments
  • Reactive Oxygen Species
  • Synaptophysin
  • amyloid beta-protein (1-42)
  • Phloroglucinol
  • Guanylate Kinases

Grant support

This work was financially supported by grants from the Korea Healthcare Technology R&D Project (HI12C0983) by the Ministry for Health, Welfare and Family Affairs of the Republic of Korea and the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education, Science and Technology (grant number 2011-0021866).