Elsevier

Neuroscience

Volume 143, Issue 4, 28 December 2006, Pages 911-922
Neuroscience

Cellular neuroscience
Metallothionein-I and -III expression in animal models of Alzheimer disease

https://doi.org/10.1016/j.neuroscience.2006.08.054Get rights and content

Abstract

Previous studies have described altered expression of metallothioneins (MTs) in neurodegenerative diseases like multiple sclerosis (MS), Down syndrome, and Alzheimer’s disease (AD). In order to gain insight into the possible role of MTs in neurodegenerative processes and especially in human diseases, the use of animal models is a valuable tool. Several transgenic mouse models of AD amyloid deposits are currently available. These models express human β-amyloid precursor protein (AβPP) carrying different mutations that subsequently result in a varied pattern of β-amyloid (Aβ) deposition within the brain. We have evaluated the expression of MT-I and MT-III mRNA by in situ hybridization in three different transgenic mice models of AD: Tg2576 (carrying AβPP harboring the Swedish K670N/M671L mutations), TgCRND8 (Swedish and the Indiana V717F mutations), and Tg-SwDI (Swedish and Dutch/Iowa E693Q/D694N mutations). MT-I mRNA levels were induced in all transgenic lines studied, although the pattern of induction differed between the models. In the Tg2576 mice MT-I was weakly upregulated in cells surrounding Congo Red-positive plaques in the cortex and hippocampus. A more potent induction of MT-I was observed in the cortex and hippocampus of the TgCRND8 mice, likely reflecting their higher amyloid plaques content. MT-I upregulation was also more significant in Tg-SwDI mice, especially in the subiculum and hippocampus CA1 area. Immunofluorescence stainings demonstrate that astrocytes and microglia/macrophages surrounding the plaques express MT-I&II. In general, MT-I regulation follows a similar but less potent response than glial fibrillary acidic protein (GFAP) expression. In contrast to MT-I, MT-III mRNA expression was not significantly altered in any of the models examined suggesting that the various MT isoforms may have different roles in these experimental systems, and perhaps also in human AD.

Section snippets

AD amyloid deposits mouse models

Tg2576 male mice (Hsiao et al., 1996) were purchased from Taconic Europe A/S (Ry, Denmark), and crossed with C57BL/6 females; female offspring 14–18 months old were used in this study (n=9 APP+/−, n=12 APP−/−). TgCRND8 male and female mice (Chisthi et al., 2001), courtesy of David Westaway (University of Toronto), were maintained on a B6C3F1/J genetic background and used at 18 months of age along age- and gender-matched controls (n=3 in the four groups). Tg-SwDI male mice (Davis et al., 2004)

Results

Fig. 1 shows representative autoradiographies for MT-I, MT-III and GFAP in situ hybridizations obtained in the Tg2576 AD model. Fig. 2 shows representative microautoradiographies. It is quite clear that, as expected, GFAP was prominently upregulated in areas surrounding amyloid plaques, which were abundantly present in the cortex and hippocampus. Quantifications carried out in the autoradiographic films in both areas demonstrated highly significant (P<0.01) increases in GFAP mRNA levels (Table 1

Discussion

Alzheimer disease, the major human neurodegenerative disease, is a progressive neurodegenerative disease of the CNS. AD is characterized by senile plaques, neurofibrillary tangles and neuronal loss. MT-I&II have consistently been shown to be upregulated in AD brains; considering what is known in several animal models of brain injury (Hidalgo et al., 2001), one could envision this response as a neuroprotective mechanism, but to test this in AD patients will be a formidable task. MT-III, on the

Acknowledgments

Support by the Ministerio de Ciencia y Tecnología and Feder (SAF2002-01268) and Ministerio de Educación y Ciencia and Feder SAF2005-00671 (J.H.) and NIH grant NS36645 (W.E.V.N.) is fully acknowledged. The support of the Lundbeck Foundation, IMK Almene Fond, Vera og Carl Michaelsens Legat, Kathrine og Vigo Skovgaards Fond, Scleroseforeningen, Karen A Tolstrup, Hørslev-fonden, Toyota Fonden, Dir. Leo Nielsens Legat, the Danish Medical Association Research Fund, the Wacherhausens Legat, Grosserer

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    Javier Carrasco and Paul Adlard contributed equally to this paper.

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