**1. Introduction**

Trimethyltin (TMT) intoxication is regarded as an appropriate model of chronic neuronal degeneration associated with cognitive impairment, and is therefore useful in the study of Alzheimer's disease (AD) [1,2]. The organotin trimethyltin chloride (TMT) is a neurotoxin that induces neuronal degeneration in the central nervous system (CNS) [3]. In particular, TMT injection leads to substantial damage of the hippocampus, which is implicated in memory [4]. Necrosis of hippocampal pyramidal cells and granule cells, produced by TMT, has been associated with the disruption of normal behavioral patterns [5], hippocampal physiological activity [6,7], and neurochemical markers of endogenous hippocampal neurotransmitters [7,8]. Rats exposed to TMT show behavioral, biochemical, and histological deficits [4]. For example, granule cells in the dentate gyrus, and cornu ammonis 1 (CA1) and cornu ammonis 3 (CA3) pyramidal cells, were significantly impregnated with TMT [9–11]. TMT intoxication attenuates hippocampal-dependent behavior in the Morris water maze [12] and the passive avoidance test [13]. TMT injection causes massive neuronal death, accompanied by enhanced hippocampal neurogenesis in the rat brain [14].

Several studies have shown that the cognitive dysfunction was associated with damaged cholinergic neurons in the brains of animal models of AD. Damage to the cholinergic system in the brain is closely associated with memory deficits. These anatomical and behavioral findings in TMT-intoxicated rats have been used to develop an attractive model of degenerative diseases such as AD [15]. AD has also been correlated with the loss of cholinergic neurons and decreased levels of acetylcholine (ACh) and choline acetyltransferase (ChAT). Lesions in these pathways lead to decreased ACh release, resulting in learning and memory dysfunction [16]. Current therapeutic measures are designed to increase levels of ACh in the brains of AD patients via suppression of acetylcholinesterase. Drugs, including the cholinesterase inhibitors, donepezil, galantamine, and rivastigmine, slow the breakdown of synaptic ACh, prolong its ability to stimulate post-synaptic receptors, and amplify the natural pattern of ACh release in the brain [17,18]. The drugs currently approved for the treatment of AD act by countering the acetylcholine deficits, leading to symptomatic relief, improved cognitive function, and enhanced acetylcholine levels in the brain.

Phosphatidylserine (PS) is the major anionic phospholipid found in the inner leaflet of eukaryotic cell membranes. PS-supplemented rodents showed enhanced memory, learning capacity, and other cognitive parameters [19]. In human studies, the efficacy of bovine-brain-derived PS (BC-PS) has been reported in patients with dementia [20]. Treatment with BC-PS improved memory function, especially delayed recall in the elderly with memory complaints. Although PS extracts from bovine cortex are known to be effective in improving memory function in humans and animals, alternative sources of PS are increasingly in demand [21]. It has been demonstrated that soybean-derived PS, one of the most promising alternatives, improved memory function in humans as much as BC-PS [22]. In addition, the treatment of rodents with BC-PS improved scopolamine-induced amnesia in the passive avoidance test, and cognitive disorders in senile subjects [23].

However, few studies have reported the effects of soybean-derived phosphatidylserine (Bean-PS) on cognitive improvement and its underlying mechanisms. The purpose of this study is to investigate whether Bean-PS prevents the neurodegeneration of the hippocampus, and the impairment of learning and memory, induced by TMT. The study demonstrated that Bean-PS improved cognitive function, and activated cholinergic systems in the hippocampus in addition to neural activation, in rats with TMT-induced cognitive deficits.
