Abstract
Brain-derived neurotrophic factor (BDNF) plays crucial roles in memory impairments including Alzheimer’s disease (AD). Previous studies have reported that tetrasialoganglioside GQ1b is involved in long-term potentiation and cognitive functions as well as BDNF expression. However, in vitro and in vivo functions of GQ1b against AD has not investigated yet. Consequently, treatment of oligomeric Aβ followed by GQ1b significantly restores Aβ1–42-induced cell death through BDNF up-regulation in primary cortical neurons. Bilateral infusion of GQ1b into the hippocampus ameliorates cognitive deficits in the triple-transgenic AD mouse model (3xTg-AD). GQ1b-infused 3xTg-AD mice had substantially increased BDNF levels compared with artificial cerebrospinal fluid (aCSF)-treated 3xTg-AD mice. Interestingly, we also found that GQ1b administration into hippocampus of 3xTg-AD mice reduces Aβ plaque deposition and tau phosphorylation, which correlate with APP protein reduction and phospho-GSK3β level increase, respectively. These findings demonstrate that the tetrasialoganglioside GQ1b may contribute to a potential strategy of AD treatment.
Highlights
Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is characterized by accumulation of senile plaques, neurofibrillary tangles, and progressive loss of memory[1]
To examine whether GQ1b has neurorestorative effects against oligomeric Aβ1–42-induced cell death through brain-derived neurotrophic factor (BDNF) up-regulation, we first investigated the effects of GQ1b on BDNF expression
Treatment with 1 μM of GQ1b for 24 h most effectively increased BDNF protein expression (Fig. 1A,B). These results did not exclude the possibility that increased BDNF expression might be caused by other gangliosides such as GT1b and GD1b, that are generated from GQ1b by membrane-associated sialidases[31]
Summary
Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is characterized by accumulation of senile plaques, neurofibrillary tangles, and progressive loss of memory[1]. Immunohistochemical staining of brain tissues from patients with Alzheimer-type dementia with an anti-GD1a ganglioside monoclonal antibody showed that GD1a presents in dystrophic neurites and senile plaques which may contribute to Aβ plaque formation[8]. Major gangliosides such as GM1, GD1a, GD1b, and GT1b are decreased, while the simple gangliosides GM2, GM3, and GD3 are increased in early and late-onset forms of AD12–15. According to our previous study, ceramide, GD1b, or GT1b did not affect BDNF protein expression. Both GM1 and GQ1b significantly increasing BDNF expression, GQ1b was more effective in increasing BDNF than GM1. Given that BDNF has crucial roles in neuroprotection and cognition[29], BDNF deficiency may hypothetically underlie Aβ-induced synaptic dysfunction and memory impairments in AD. Recent studies have supported this hypothesis by demonstrating that BDNF gene delivery or recombinant BDNF infusion reverses cognitive decline in rodent and primate models of AD without affecting Aβ pathology[30]
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