Lead and IQ: Toxic effects and tau protein

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  • Published: Nov 15, 2012
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Heavy metal exposure

Microtubule-associated tau protein via Wikimedia

An atomic absorption spectroscopy (AAS) study has demonstrated that exposure to the heavy metal lead increases phosphorylation of the tau protein in the brains of laboratory rats. The study offers new insights into the biochemical link between this process, lead exposure and cognitive impairment.

It has long been known that exposure to the heavy metal lead early in life can be detrimental to cognitive development leading to a lower than expected IQ in some children. Understanding why this should be so has remained somewhat unclear. It was, however, also known that hyperphosphorylation of the tau phospho-protein in the brain can also lead to similar, perhaps the same kind of, cognitive impairment.

Phosphorylation of tau is regulated by various kinase enzymes during development and growth to regulate microtubules. The biochemistry apparently goes awry if hyperphosphorylation occurs. Neurite growth and synaptogenesis, for instance, require intact microtubule structure and in hyperphosphorylation these are disrupted because the tau protein can no longer effectively bind to the microtubules to stabilise them. This failed process has been associated with neuronal cell death and memory loss.

Indeed, tau protein, which is associated with the stabilisation of axonal microtubules in the central nervous system, has previously also been implicated in neurodegenerative diseases such as Alzheimer's disease, some forms of frontotemporal lobar degeneration, and chronic traumatic encephalopathy. 

The secret of tau

Now, Abdur Rahman, Khalid Khan, Ghanim Al-Khaledi, Islam Khan and Sreeja Attur of Kuwait University Department of Family Sciences, College for Women have investigated the possible link between lead exposure and tau phosphorylation in Wistar rats. The brains of Wistar rat pups exposed to 0.2% lead acetate in their drinking water for three weeks after birth were analysed by AAS for the presence of lead and via Western blot for expression of tau, phosphorylated tau and various serine/threonine protein phosphatases (PP1, PP2A, PP2B and PP5). The team also observed whether or not learning impairment was apparent in the developing rats.

The team reports that learning was indeed impaired because of the lead exposure and that there was also a significant reduction in the expression of tau but an increase in phosphorylation of tau at three specific amino acid groupings in the protein: Ser199/202, Thr212/Ser214 and Thr231. They found that PP2A expression was lower in the rat pups exposed to lead, whereas PP1 and PP5 expression were at raised levels.

"These results demonstrate that early postnatal exposure to lead decreases PP2A expression and induces tau hyperphosphorylation at several serine and threonine residues," the team says. This they suggest offers an explanation for lead-induced learning and memory deficits because it triggers hyperphosphorylation of tau protein. 

Phosphorylation, the name of the game

Tau phosphorylation by lead exposure was previously reported in a mouse model by Li et al (Acta Biol Hung 61(2):123-134)) and Rahman and colleagues showed in 2011 that human fetal neurons can be affected. "We are the first group to show that learning impairment by lead exposure involves over expression/over-activation of protein phosphatases, PP1 and PP2A," Rahman told SpectroscopyNOW.

"We have shown for the first time that over expression of PP1 by lead exposure is associated with learning and long-term memory impairment whereas PP2A over-activation is associated with short-term memory impairment. He adds that the team's aim is to fully investigate the pathway(s) that leads to the over-activation of these phosphatases and to find relevant therapeutic strategies to overcome the problem of learning and memory impairment by lead exposure which is widespread in many countries. 

Related Links

Acta Biol Hung 2012, 63, 411-425: "Early postnatal lead exposure induces tau phosphorylation in the brain of young rats"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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