Evidence for widespread, severe brain copper deficiency in Alzheimer's dementia

Abstract

Datasets comprising simultaneous measurements of many essential metals in Alzheimer's disease (AD) brain are sparse, and available studies are not entirely in agreement. To further elucidate this matter, we employed inductively-coupled-plasma mass spectrometry to measure post-mortem levels of 8 essential metals and selenium, in 7 brain regions from 9 cases with AD (neuropathological severity Braak IV-VI), and 13 controls who had normal ante-mortem mental function and no evidence of brain disease. Of the regions studied, three undergo severe neuronal damage in AD (hippocampus, entorhinal cortex and middle-temporal gyrus); three are less-severely affected (sensory cortex, motor cortex and cingulate gyrus); and one (cerebellum) is relatively spared. Metal concentrations in the controls differed among brain regions, and AD-associated perturbations in most metals occurred in only a few: regions more severely affected by neurodegeneration generally showed alterations in more metals, and cerebellum displayed a distinctive pattern. By contrast, copper levels were substantively decreased in all AD-brain regions, to 52.8-70.2% of corresponding control values, consistent with pan-cerebral copper deficiency. This copper deficiency could be pathogenic in AD, since levels are lowered to values approximating those in Menkes' disease, an X-linked recessive disorder where brain-copper deficiency is the accepted cause of severe brain damage. Our study reinforces others reporting deficient brain copper in AD, and indicates that interventions aimed at safely and effectively elevating brain copper could provide a new experimental-therapeutic approach.

Effects of Alzheimer’s disease and formalin fixation on the different mineralised-iron forms in the human brain

“…The wet-to-dry weight ratio (R wd ) for the AD samples was 5.9 ± 0.2, which was very similar to that of the healthy controls: R wd = 6.2 ± 0.2. These numbers are in agreement with a previous study which reported no difference in R wd between AD and controls 28 , and when formalin-fixed tissue is used 29 , since formalin fixation does not alter the total water content of the tissue 30 . However, it is worth noting that the white matter contains consistently less, i.e.…”

“…However, the authors failed to found the same difference in the inferior temporal cortex which, on the other hand, reported iron levels correlating with antecedent cognitive decline in those individuals who had underlying plaque and tangle pathology 37 . Total iron levels are known to increase in different brain areas of AD cases 28 , with the temporal cortex being one of the most and earliest affected regions 24,38 . It is not yet clear what the underlying phenomena leading to brain iron accumulation in the context of AD are.…”

Mass spectrometry is a multifaceted weapon to be used in the battle against Alzheimer's disease: Amyloid beta peptides and beyond

“…Moreover, extraction of samples from specific areas of the brain allows one to determine metal ion concentration differences among the various parts of the brain, to provide an insight into metal distributions between control and AD patients for each brain area. Indeed, because of cessation of blood circulation after death, metals cannot be exchanged post‐mortem among the various tissues so that a spatial picture of metal distributions in the brain is feasible . Intriguing findings with ICP‐MS show that Zn levels are elevated in many areas of AD brains, in accordance with a situation of increased Zn 2+ sequestration in heavily affected brain regions to cause functional unavailability of this metal ion for physiological processes in other areas, regardless of any increase in total tissue‐Zn.…”

“…Intriguing findings with ICP‐MS show that Zn levels are elevated in many areas of AD brains, in accordance with a situation of increased Zn 2+ sequestration in heavily affected brain regions to cause functional unavailability of this metal ion for physiological processes in other areas, regardless of any increase in total tissue‐Zn. On the contrary, although Cu increase or decrease in AD brains is still a matter of debate, Cu levels have been reported to be depleted in many areas of AD brains to possibly have a significant impact on cellular energy production, as well as to increase oxidative damage in AD brain by impairing Cu‐mediated antioxidant defences such as those catalyzed by superoxide dismutase (SOD) …”

“…On the contrary, although Cu increase or decrease in AD brains is still a matter of debate, 128,129 Cu levels have been reported to be depleted in many areas of AD brains 130 to possibly have a significant impact on cellular energy production, as well as to increase oxidative damage in AD brain by impairing Cu-mediated antioxidant defences such as those catalyzed by superoxide dismutase (SOD). 127 Although the examples reported above demonstrates the possibility to apply LA-ICP-MS for bio-imaging metals concentrations of various brain areas, the limits of this approach must be taken into account. Besides the matrix effects that can be partially overcome with multipoint calibrations constructed from matrix-matched standards 131 or the double isotope dilution strategy, 132 we highlight that mapping metal ions concentrations of the brain still remains a challenging task also because of sensitivity issues 133 ; only results obtained with the same experimental techniques from different areas should be compared.…”