Characterization of the role of metallothionein-3 in an animal model of Alzheimer’s disease

Abstract

Among the dementias, Alzheimer's disease (AD) is the most commonly diagnosed, but there are still no effective drugs available for its treatment. It has been suggested that metallothionein-3 (MT-3) could be somehow involved in the aetiology of AD, and in fact very promising results have been found in in vitro studies, but the role of MT-3 in vivo needs further analysis. In this study we analyzed the role of MT-3 in a mouse model of AD, Tg2576 mice, which overexpress human Amyloid Precursor Protein (hAPP) with the Swedish mutation.MT-3 deficiency partially rescued the APP-induced mortality of females, and mildly affected APP-induced changes in behavior assessed in the hole-board and plus-maze tests in a gender-dependent manner. Amyloid plaque burden and/or hAPP expression were decreased in the cortex and hippocampus of MT-3 deficient females. Interestingly, exogenously administered Zn 7 MT-3 increased soluble Aβ40 and Aβ42 and amyloid plaques and gliosis, particularly in the cortex, and changed several behavioral traits (increased deambulation and exploration and decreased anxiety). These results highlight that the control of the endogenous production and/or action of MT-3 could represent a powerful therapeutic target in AD.

Metallothionein, Copper and Alpha-Synuclein in Alpha-Synucleinopathies

“…Indeed, extracellular alpha-synuclein inhibits β-amyloid plaque formation (Bachhuber et al, 2015), a process that may also be influenced by extracellular MT binding (De Ricco et al, 2015b). Further, in a mouse model of AD, MT-3- and MT-1/2-deficient mice had lower plaque burdens and mortality, and performed better in behavioral tests (Manso et al, 2012a,b). Figure 2 summarizes the interplay between MT, alpha-synuclein and copper in different cell types in PD.…”

Zinc and the aging brain

“…(3) Zinc stimulates kinases and inhibits protein phosphatases leading to phosphorylation of Tau which promotes the aggregation of Tau in neurofibrillary tangles (NFT) and contributes to a positive feedback loop that further increases postsynaptic calcium influx through NMDARs resulting in neuronal cell death synaptic activity in the APP/PS1 mouse model and direct application of soluble Ab dimers to CA1 neurons increases synaptic activity in wild type mice measured in vivo by calcium imaging (Busche et al 2012). Deficiency of the zinc transporter ZnT3 or the brain specific zinc binding protein metallothionein (MT)3 can prevent deposition of Ab in Swedish mutant APP mice (Lee et al 2002;Manso et al 2012), and senile plaques form preferentially in zinc enriched cortical layers of APP/PS1 mice (Stoltenberg et al 2007). These findings provide further evidence that zinc released from synaptic vesicles could contribute to AD pathology.…”

Absence of metallothionein-3 produces changes on MT-1/2 regulation in basal conditions and alters hypothalamic-pituitary–adrenal (HPA) axis

“…We also obtain contradictory results in our lab. Body weight progression from 22 weeks to 62 weeks of age did not show any differences between Mt-3 null and WT mice in either gender (Manso et al, 2012) but in other experiments (unpublished data) when Mt-3-null mice were fed with a high-fat-diet (HFD) both genders developed obesity compared to controls. These results suggest that MT-3 could play a role in metabolic regulation but further studies of genetic background effect in this regard are necessary.…”