Copper To The Rescue?

Dr. Jane Flinn

        Our lecturer this week was Dr. Jane M. Flinn, director of undergraduate neuroscience program at George Mason University. Dr. Flinn's current research focuses on the role of metals in normal memory and in Alzheimer's disease (AD). The brain of those with AD contains plaques and tangles. The plaques contain amyloid, a protein which is aggregated by zinc, but which also binds copper and iron.

        Recently, she observed elevated levels of zinc, iron and copper in the plaques found in brains of people with AD.  The transgenic mice she experimented with carried an APP mutation so unlike most mice, they developed plaques. By administering different levels of metals in their drinking water, her team's results showed "both zinc and iron significantly impaired spatial memory in mice modeling early onset AD but copper partially remediated the zinc effect." Additionally, increased zinc diminishes the ability to learn that a stimulus is no longer fearful in normal mice and rats. This effect can be a model of post-traumatic stress disorder (PTSD). Small amounts of copper have been shown to partially alleviate these symptoms. Perhaps learning impairment could be a result of copper deficiency?

A soldier affected by PTSD

        Previous research have demonstrated chronic stress decreases zinc in the blood while increases it in the brain. This suggests zinc might be redistributed from the blood to the brain. Results from other previous research showed excess zinc both pre and post-natally demonstrated impairments in fear extinction thus zinc may be a mediator between stress and the inability to extinguish fear.

        Dr. Flinn conducted the experiment, The Effects of Chronic Unpredictable Stress (CUS) on the Ability to Extinguish Fear: Zinc as a Mediator, where they collected data from mice given zinc and measured impairments in fear extinction. The subjects were 31 Sprague-Dawley rats bred both pre and post-natally on either water enhanced with zinc (10mg/kg ZnCO3) or tap water. The four groups were: tap water + stress (control), tap water + stress, zinc + no stress, zinc + stress. A 21 day randomized chronic unpredictable stress paradigm was administered. 10 days post stress, cued fear conditioning was conducted. Day 1: training = 3 tone + shock pairings. Day 2: extinction = 18 tones and no shock. Day 3: recall = 18 tones and no shock.

Representative metal output images. Images show iron
(Fe, top left), calcium (Ca, top right),
zinc (Zn, bottom left), and potassium (K, bottom right).
(White color= greatest concentration).

        Dr. Flinn and her team concluded the zinc group took longer to learn fear extinction as well as memory deficits with impairment of recall. CUS rats showed less freezing when anticipating shocks compared to control group. This concludes a down regulation of the HPA axis even 10 days post termination of stress.

         The work of Dr. Flinn will guide future directions of these types of research. If increased Zinc in the diet can cause deficiency, are the deficits in the fear conditioning due to a copper deficiency? Thus far we think the deficits in AD are due to a copper deficiency, continuing work on developing mouse model of late onset AD would confirm or reject this hypothesis. It is suggested that AD is caused by an inflammation problem. Dr. Flinn mentioned an incident where there were two identical twins and one of them took aspirin regularly. The other developed AD 10 years sooner than the twin on the aspirin regimen. This, again, raises new question that will hopefully be answered with further research.

Reference

The Effects of Chronic Unpredictable Stress (CUS) on the Ability to Extinguish Fear: Zinc as a Mediator

Knaack, G.L., McDonald, C.G., & Flinn, J.M. Dept. Psychology, George Mason Univ., Fairfax, VA, USA