Metallothioneins (MTs) are low molecular weight, zinc- and copper-binding, antioxidant proteins. MT-1&2 isoforms are highly inducible by brain injury, and have been reported to be increased in major human neurodegenerative/neuroinflammatory diseases such as Alzheimer diseases (AD) and multiple sclerosis (MS). MT-3 isoform shows a distinct pattern of responses and putative functions.

In the brain, MT-1&2 are upregulated mainly in reactive astrocytes and microglia/macrophages in animal models of traumatic brain injury, MS and AD. Results in knock-out mice demonstrate a major role of these proteins controlling oxidative stress, inflammation and neuronal survival, although the mechanisms are poorly understood. A new mechanism is proposed that consists of MT secretion by astrocytes and neuronal uptake through the multicarrier protein megalin. This uptake promotes neurite outgrowth in vitro and axonal growth in the optic nerve transaction surgery model.

MT-1&2 but not MT-3 are upregulated in several mouse models of AD, suggesting that the former isoforms might be relevant, but the latter isoform cannot be ruled out. Thus, the role of all these MT isoforms in a mouse AD model is being tested by crossing APP2576 mice with either Mt1&2 KO or Mt3 KO mice or TgMT-I mice (which carry 56 copies of a minimally mutated MT-1 isoform). So far the results demonstrate that all MT isoforms do affect the mortality rate of the APP2576 mice well before amyloid plaques are formed.

In conclusion, very encouraging results are found which support a major role of metallothioneins in animal models of neuroinflammation including AD mouse models.