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

Eun-Jeong Yang,Moon-Jeong Chang,Junghwa Ryu,Jin-Won Hyun,Young Hae Chong,Moon-Seok Choi,Hye-Sun Kim,Shinkyu Choi,Sangzin Ahn,Madepalli K Lakshmana

doi:10.1371/journal.pone.0135686

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.

Highlights

Alzheimer’s disease (AD) is the most common form of irreversible dementia, and can be neuropathologically identified by the hall mark lesions of AD; senile plaques consisting of extracellular deposits of Aβ and neurofibrillary tangles by accumulation of abnormal filaments of tau [1,2,3,4,5,6]
We investigated the therapeutic effects of phloroglucinol on AD and demonstrated that phloroglucinol reduces oxidative stress induced by oligomeric Aβ1–42 (Aβ1– 42) in the HT-22, hippocampal cell line
We evaluated whether phloroglucinol itself was toxic to the HT-22 cells and rat primary hippocampal neuron cultures by employing MTT and Latate dehydrogenase (LDH) assays

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of irreversible dementia, and can be neuropathologically identified by the hall mark lesions of AD; senile plaques consisting of extracellular deposits of Aβ and neurofibrillary tangles by accumulation of abnormal filaments of tau [1,2,3,4,5,6]. AD principally targets synapses, by which synaptic loss and dysfunction show strong connection to cognitive impairments in AD [7]. Oxidative stress results from an imbalance between antioxidant defenses and the intracellular accumulation of ROS, which may contribute to memory and cognitive function deficits in AD. Recent studies reported that this redox imbalance increases the production of amyloid beta peptide (Aβ) [9], thereby producing ROS, which act as a pro-oxidant to induce neuronal death in AD [10]. Human AD brains have displayed an increase in the levels of oxidative stress markers and ROS production, negatively affecting synaptic plasticity [11,12,13,14].

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