Elevation of brain glucose and polyol-pathway intermediates with accompanying brain-copper deficiency in patients with Alzheimer's disease: metabolic basis for dementia.
Impairment of brain-glucose uptake and brain-copper regulation occurs in Alzheimer's disease (AD). Here we sought to further elucidate the processes that cause neurodegeneration in AD by measuring levels of metabolites and metals in brain regions that undergo different degrees of damage. We employed mass spectrometry (MS) to measure metabolites and metals in seven post-mortem brain regions of nine AD patients and nine controls, and plasma-glucose and plasma-copper levels in an ante-mortem case-control study. Glucose, sorbitol and fructose were markedly elevated in all AD brain regions, whereas copper was correspondingly deficient throughout (all P < 0.0001). In the ante-mortem case-control study, by contrast, plasma-glucose and plasma-copper levels did not differ between patients and controls. There were pervasive defects in regulation of glucose and copper in AD brain but no evidence for corresponding systemic abnormalities in plasma. Elevation of brain glucose and deficient brain copper potentially contribute to the pathogenesis of neurodegeneration in AD.
School of Biological Sciences, and Maurice Wilkins Centre for Molecular Biodiscovery, Faculty of Science, University of Auckland, New Zealand.|Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.|Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, and Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom.
Jingshu
J
Xu
Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, and Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom.
Paul
P
Begley
Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, and Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom.
Stephanie J
SJ
Church
School of Biological Sciences, and Maurice Wilkins Centre for Molecular Biodiscovery, Faculty of Science, University of Auckland, New Zealand.|Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.|Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, and Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom.
Stefano
S
Patassini
Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, and Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom.
Selina
S
McHarg
Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, and Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom.
Nina
N
Kureishy
Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, and Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom.
Katherine A
KA
Hollywood
Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
Henry J
HJ
Waldvogel
School of Biological Sciences, and Maurice Wilkins Centre for Molecular Biodiscovery, Faculty of Science, University of Auckland, New Zealand.
Hong
H
Liu
School of Biological Sciences, and Maurice Wilkins Centre for Molecular Biodiscovery, Faculty of Science, University of Auckland, New Zealand.
Shaoping
S
Zhang
Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, and Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom.
Wanchang
W
Lin
Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom.
Karl
K
Herholz
Anatomical Pathology, LabPLUS, Auckland City Hospital, Auckland, New Zealand.
Clinton
C
Turner
Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.|Anatomical Pathology, LabPLUS, Auckland City Hospital, Auckland, New Zealand.
Beth J
BJ
Synek
Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
Maurice A
MA
Curtis
Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom.
Jack
J
Rivers-Auty
Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom.
Catherine B
CB
Lawrence
Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom.
Katherine A B
KA
Kellett
Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom.
Nigel M
NM
Hooper
Salford Royal NHS Foundation Trust, Salford, United Kingdom.
Emma R L C
ER
Vardy
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Donghai
D
Wu
Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, and Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom.
Richard D
RD
Unwin
Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
Richard L M
RL
Faull
Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, and Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom.
Andrew W
AW
Dowsey
School of Biological Sciences, and Maurice Wilkins Centre for Molecular Biodiscovery, Faculty of Science, University of Auckland, New Zealand.|Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.|Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, and Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom.
Garth J S
GJ
Cooper
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D003300:Copper / Q000097:blood / Q000172:deficiency*; D003704:Dementia / Q000378:metabolism*; D005260:Female; D005632:Fructose / Q000737:chemistry; D005947:Glucose / Q000737:chemistry; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008670:Metals / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D011108:Polymers / Q000737:chemistry*; D011336:Probability; D051381:Rats; D017208:Rats, Wistar; D013012:Sorbitol / Q000737:chemistry; D014018:Tissue Distribution
D001786:Blood Glucose; D008670:Metals; D011108:Polymers; C024617:polyol; D005632:Fructose; D013012:Sorbitol; D003300:Copper; D005947:Glucose