Presenilins Promote the Cellular Uptake of Copper and Zinc and Maintain Copper Chaperone of SOD1-dependent Copper/Zinc Superoxide Dismutase Activity

Abstract

Dyshomeostasis of extracellular zinc and copper has been implicated in ␤-amyloid aggregation, the major pathology associated with Alzheimer disease. Presenilin mediates the proteolytic cleavage of the ␤-amyloid precursor protein to release ␤-amyloid, and mutations in presenilin can cause familial Alzheimer disease. We tested whether presenilin expression affects copper and zinc transport. Studying murine embryonic fibroblasts (MEFs) from presenilin knock-out mice or RNA interference of presenilin expression in HEK293T cells, we observed a marked decrease in saturable uptake of radiolabeled copper and zinc. Measurement of basal metal levels in 6-monthold presenilin 1 heterozygous knock-out (PS1 ؉/؊ ) mice revealed significant deficiencies of copper and zinc in several tissues, including brain. Copper/zinc superoxide dismutase (SOD1) activity was significantly decreased in both presenilin knock-out MEFs and brain tissue of presenilin 1 heterozygous knock-out mice. In the MEFs and PS1 ؉/؊ brains, copper chaperone of SOD1 (CCS) levels were decreased. Zinc-dependent alkaline phosphatase activity was not decreased in the PS null MEFs. These data indicate that presenilins are important for cellular copper and zinc turnover, influencing SOD1 activity, and having the potential to indirectly impact ␤-amyloid aggregation through metal ion clearance.

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…A disintegrin and metalloproteinase domain-containing protein 10, the α-secretase involved in the physiological processing of APP, is a zinc-dependent enzyme and zinc increases APP proteolysis [86], while zinc inhibits γ-secretase activity [87]. Zinc also increase PS1 expression, and presenilin protein also facilitates cellular zinc uptake [88]. Finally, Aβ bound to zinc is resistant to proteolysis by zinc-dependent matrix metalloproteases [89,90].…”

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

“…Lithium (at nontoxic concentrations 29 ) induced significant iron accumulation within 18 h in a dose-dependent manner (5 mm Li: +48%, P=0.005; 10 mm Li: +56%, P<0.001; Figure 3a), but did not alter copper or zinc levels ( Figure 3b), consistent with the changes in brain levels of these metals in mice treated with lithium ( Figure 2c). Lithium (10 mm) significantly inhibited the efflux of iron (chased after 59 Fe loading)…”

Low levels of copper disrupt brain amyloid-β homeostasis by altering its production and clearance

“…Cu slowly enters brain parenchyma and cerebrospinal fluid (CSF) when the cerebrovasculature is perfused, in situ, with free Cu (41). Cu transport presumably occurs via Cu transporter 1 (Ctr1) and/or divalent metal transporter 1 (DMT1) on the luminal surface, and ATP7A, a Cu ATPase transporter, on the abluminal surface of the BBB (42) or presenilins (43). In our in vitro studies, we used levels of Cu comparable to the normal non-Cp-bound Cu fraction in plasma and twofold lower than Cu levels normally found in the human CSF (3,11).…”