Alzheimer risk factors age and female sex induce cortical Aβ aggregation by raising extracellular zinc

被引:19
作者
Datki, Zsolt [1 ]
Galik-Olah, Zita [1 ]
Janosi-Mozes, Emese [1 ]
Szegedi, Viktor [2 ]
Kalman, Janos [1 ]
Hunya, Akos Gabor [3 ]
Fulop, Livia [3 ]
Tamano, Haruna [4 ]
Takeda, Atsushi [4 ]
Adlard, Paul A. [5 ,6 ]
Bush, Ashley, I [5 ,6 ]
机构
[1] Univ Szeged, Dept Psychiat, H-6725 Szeged, Hungary
[2] Univ Szeged, Dept Physiol Anat & Neurosci, H-6726 Szeged, Hungary
[3] Univ Szeged, Dept Med Chem, H-6726 Szeged, Hungary
[4] Univ Shizuoka, Sch Pharmaceut Sci, Dept Neurophysiol, Suruga Ku, 52-1 Yada, Shizuoka 4228526, Japan
[5] Melbourne Dementia Res Ctr, Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3052, Australia
[6] Univ Melbourne, Parkville, Vic 3052, Australia
基金
英国医学研究理事会;
关键词
HISTOCHEMICALLY-REACTIVE ZINC; ACUTE HIPPOCAMPAL SLICES; LONG-TERM POTENTIATION; AMYLOID PLAQUES; SYNAPTIC ZINC; TRANSGENIC MICE; SENILE PLAQUE; BRAIN-SLICES; DISEASE; NEURONS;
D O I
10.1038/s41380-020-0800-y
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Aging and female sex are the major risk factors for Alzheimer's disease and its associated brain amyloid-beta (A beta) neuropathology, but the mechanisms mediating these risk factors remain uncertain. Evidence indicates that A beta aggregation by Zn(2+)released from glutamatergic neurons contributes to amyloid neuropathology, so we tested whether aging and sex adversely influences this neurophysiology. Using acute hippocampal slices, we found that extracellular Zn2+-elevation induced by high K(+)stimulation was significantly greater with older (65 weeks vs 10 weeks old) rats, and was exaggerated in females. This was driven by slower reuptake of extracellular Zn2+, which could be recapitulated by mitochondrial intoxication. Zn2+:A beta aggregates were toxic to the slices, but A beta alone was not. Accordingly, high K(+)caused synthetic human A beta added to the slices to form soluble oligomers as detected by bis-ANS, attaching to neurons and inducing toxicity, with older slices being more vulnerable. Age-dependent energy failure impairing Zn(2+)reuptake, and a higher maximal capacity for Zn(2+)release by females, could contribute to age and sex being major risk factors for Alzheimer's disease.
引用
收藏
页码:2728 / 2741
页数:14
相关论文
共 83 条
  • [1] Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Aβ
    Adlard, Paul A.
    Cherny, Robert A.
    Finkelstein, David I.
    Gautier, Elisabeth
    Robb, Elysia
    Cortes, Mikhalina
    Volitakis, Irene
    Liu, Xiang
    Smith, Jeffrey P.
    Perez, Keyla
    Laughton, Katrina
    Li, Qiao-Xin
    Charman, Susan A.
    Nicolazzo, Joseph A.
    Wilkins, Simon
    Deleva, Karolina
    Lynch, Toni
    Kok, Gaik
    Ritchie, Craig W.
    Tanzi, Rudolph E.
    Cappai, Roberto
    Masters, Colin L.
    Barnham, Kevin J.
    Bush, Ashley I.
    [J]. NEURON, 2008, 59 (01) : 43 - 55
  • [2] Metal chaperones prevent zinc-mediated cognitive decline
    Adlard, Paul A.
    Parncutt, Jacqui
    Lal, Varsha
    James, Simon
    Hare, Dominic
    Doble, Philip
    Finkelstein, David I.
    Bush, Ashley I.
    [J]. NEUROBIOLOGY OF DISEASE, 2015, 81 : 196 - 202
  • [3] A novel approach to rapidly prevent age-related cognitive decline
    Adlard, Paul A.
    Sedjahtera, Amelia
    Gunawan, Lydia
    Bray, Lisa
    Hare, Dominic
    Lear, Jessica
    Doble, Philip
    Bush, Ashley I.
    Finkelstein, David I.
    Cherny, Robert A.
    [J]. AGING CELL, 2014, 13 (02) : 351 - 359
  • [4] Cognitive Loss in Zinc Transporter-3 Knock-Out Mice: A Phenocopy for the Synaptic and Memory Deficits of Alzheimer's Disease?
    Adlard, Paul A.
    Parncutt, Jacqui M.
    Finkelstein, David I.
    Bush, Ashley I.
    [J]. JOURNAL OF NEUROSCIENCE, 2010, 30 (05) : 1631 - 1636
  • [5] Anderson CT, 2015, P NATL ACAD SCI USA
  • [6] Dramatic aggregation of Alzheimer Aβ by Cu(II) is induced by conditions representing physiological acidosis
    Atwood, CS
    Moir, RD
    Huang, XD
    Scarpa, RC
    Bacarra, NME
    Romano, DM
    Hartshorn, MK
    Tanzi, RE
    Bush, AI
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (21) : 12817 - 12826
  • [7] Characterization of copper interactions with Alzheimer amyloid β peptides:: Identification of an attomolar-affinity copper binding site on amyloid β1-42
    Atwood, CS
    Scarpa, RC
    Huang, XD
    Moir, RD
    Jones, WD
    Fairlie, DP
    Tanzi, RE
    Bush, AI
    [J]. JOURNAL OF NEUROCHEMISTRY, 2000, 75 (03) : 1219 - 1233
  • [8] Ayton S., 2019, MOL PSYCHIATR, V45, P358
  • [9] ZnT3 mRNA levels are reduced in Alzheimer's disease post-mortem brain
    Beyer, Nancy
    Coulson, David T. R.
    Heggarty, Shirley
    Ravid, Rivka
    Irvine, G. Brent
    Hellemans, Jan
    Johnston, Janet A.
    [J]. MOLECULAR NEURODEGENERATION, 2009, 4
  • [10] RAPID INDUCTION OF ALZHEIMER A-BETA AMYLOID FORMATION BY ZINC
    BUSH, AI
    PETTINGELL, WH
    MULTHAUP, G
    PARADIS, MD
    VONSATTEL, JP
    GUSELLA, JF
    BEYREUTHER, K
    MASTERS, CL
    TANZI, RE
    [J]. SCIENCE, 1994, 265 (5177) : 1464 - 1467