Altered microglial copper homeostasis in a mouse model of Alzheimer's disease.
Alzheimer's disease (AD) is characterized by progressive neurodegeneration associated with the aggregation and deposition of β-amyloid (Aβ(40) and Aβ(42) ) peptide in senile plaques. Recent studies suggest that copper may play an important role in AD pathology. Copper concentrations are elevated in amyloid plaques and copper binds with high affinity to the Aβ peptide and promotes Aβ oligomerization and neurotoxicity. Despite this connection between copper and AD, it is unknown whether the expression of proteins involved in regulating copper homeostasis is altered in this disorder. In this study, we demonstrate that the copper transporting P-type ATPase, ATP7A, is highly expressed in activated microglial cells that are specifically clustered around amyloid plaques in the TgCRND8 mouse model of AD. Using a cultured microglial cell line, ATP7A expression was found to be increased by the pro-inflammatory cytokine interferon-gamma, but not by TNF-α or IL-1β. Interferon-gamma also elicited marked changes in copper homeostasis, including copper-dependent trafficking of ATP7A from the Golgi to cytoplasmic vesicles, increased copper uptake and elevated expression of the CTR1 copper importer. These findings suggest that pro-inflammatory conditions associated with AD cause marked changes in microglial copper trafficking, which may underlie the changes in copper homeostasis in AD. It is concluded that copper sequestration by microglia may provide a neuroprotective mechanism in AD.
Zheng
Zhiqiang
Z
Department of Nutritional Sciences and Exercise Physiology, University of Missouri, Columbia, Missouri 65211-7310, USA.
White
Carine
C
Lee
Jaekwon
J
Peterson
Troy S
TS
Bush
Ashley I
AI
Sun
Grace Y
GY
Weisman
Gary A
GA
Petris
Michael J
MJ
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000378:metabolism; D002460:Cell Line; D003300:Copper / Q000378:metabolism*; D000079923:Copper Transporter 1; D000073840:Copper-Transporting ATPases; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D006706:Homeostasis; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport
C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; C490077:Slc31a1 protein, mouse; D003300:Copper; D007371:Interferon-gamma; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases