Abstract
Alzheimer’s disease (AD) is one of the leading causes of death for people over 65 years. Worse still, no completely effective therapeutic agent is available so far. One important pathological hallmark of AD is accumulated amyloid-β (Aβ) plaques with dysregulated metal homeostasis. Human metallothionin 3 (MT3), a regulator of metal homeostasis, is downregulated at least 30% in AD brain. So far, some in vitro studies demonstrated its multiple functions related to AD. However, it is a great pity that systematic in vivo studies of MT3 on AD model animals are still a blank so far. In this study, we treated APP/PS1 mice with sustained drug release of Zn7MT3 directly to the central nervous system, and investigated the role and molecular mechanism of Zn7MT3 to protect against AD mice systematically. The results demonstrated that Zn7MT3 can significantly ameliorate cognitive deficits, regulate metal homeostasis, abolish Aβ plaque load, and reduce oxidative stress. Additionally, it has been confirmed that MT3 is penetrable to the blood brain barrier of AD mice. All these results support that Zn7MT3 is an effective AD suppressing agent and has potential for applications in Alzheimer’s disease therapy.
Highlights
Alzheimer’s disease (AD) is the most frequent form of neurodegenerative disease, which accounts for 60–70% of dementia cases[1]
Memory retention was found to be affected by Zn7MT3 as confirmed by probe trial, in which Tg-Zn7MT3 mice presented significantly more crossing numbers and time spent in target quadrant (Fig. 1B,C), while the swimming speed of each group were similar
We excluded the potential impediment of the blood brain barrier (BBB), ensured the arrival of Zn7MT3 to central nervous system (CNS) and guaranteed the physiological changes we observed originated from the effect in brain rather than the peripheral blood circulation
Summary
Alzheimer’s disease (AD) is the most frequent form of neurodegenerative disease, which accounts for 60–70% of dementia cases[1]. Hye Gwang Jeong suggested MT3 regulated the non-amyloidogenic pathway by conversing ADAM10 into its active form, resulting in increased sAPPα and reduced Aβ peptide levels[19] These results above demonstrated the important multiple functions of MT3 to AD, they are in vitro studies limited to the molecular or cellular level, failing to reflect how MT3 plays its combined comprehensive role on the typical symptoms of AD. Whether MT3 possesses curative effect to AD can only be further explained by in vivo studies, and how it exerts its multiple functions in brain including the influence on metal homeostasis, Aβ deposits and neuron apoptosis should be explored in detail on animal models. All these reasons above drive us to further elucidate how MT3 exerts its role in AD brain and whether it processes promising effective therapeutic potential
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