Extracellular Zn 2+ Is Essential for Amyloid β 1-42 -Induced Cognitive Decline in the Normal Brain and Its Rescue

• Published in: The Journal of neuroscience Vol. 37; no. 30; pp. 7253 - 7262
• Main Authors: Takeda, Atsushi, Tamano, Haruna, Tempaku, Munekazu, Sasaki, Miku, Uematsu, Chihiro, Sato, Shoko, Kanazawa, Hiroaki, Datki, Zsolt L, Adlard, Paul A, Bush, Ashley I
• Format: Journal Article
• Language: English
• Published: United States 26-07-2017
• Subjects: Amyloid beta-Peptides - metabolism; Animals; Cognitive Dysfunction - complications; Cognitive Dysfunction - metabolism; Disease Progression; Extracellular Fluid - metabolism; Hippocampus - metabolism; Long-Term Potentiation; Male; Memory Disorders - complications; Memory Disorders - metabolism; Peptide Fragments - metabolism; Protein Binding; Rats; Rats, Wistar; Zinc - metabolism; extracellular Zn2; dentate gyrus; cognitive decline; Aβ1–42
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.0954-17.2017

Brain Aβ
accumulation is considered an upstream event in pathogenesis of Alzheimer's disease. However, accumulating evidence indicates that other neurochemical changes potentiate the toxicity of this constitutively generated peptide. Here we report that the interaction of Aβ
with extracellular Zn
is essential for
rapid uptake of Aβ
and Zn
into dentate granule cells in the normal rat hippocampus. The uptake of both Aβ
and Zn
was blocked by CaEDTA, an extracellular Zn
chelator, and by Cd
, a metal that displaces Zn
for Aβ
binding.
perforant pathway LTP was unaffected by perfusion with 1000 nm Aβ
in ACSF without Zn
However, LTP was attenuated under preperfusion with 5 nm Aβ
in ACSF containing 10 nm Zn
, recapitulating the concentration of extracellular Zn
, but not with 5 nm Aβ
in ACSF containing 10 nm Zn
Aβ
and Zn
were not taken up into dentate granule cells under these conditions, consistent with lower affinity of Aβ
for Zn
than Aβ
Aβ
-induced attenuation of LTP was rescued by both CaEDTA and CdCl
, and was observed even with 500 pm Aβ
Aβ
injected into the dentate granule cell layer of rats induced a rapid memory disturbance that was also rescued by coinjection of CdCl
The present study supports blocking the formation of Zn-Aβ
in the extracellular compartment as an effective preventive strategy for Alzheimer's disease.
Short-term memory loss occurs in normal elderly and increases in the predementia stage of Alzheimer's disease (AD). Amyloid-β
(Aβ
), a possible causing peptide in AD, is bound to Zn
in the extracellular compartment in the hippocampus induced short-term memory loss in the normal rat brain, suggesting that extracellular Zn
is essential for Aβ
-induced short-term memory loss. The evidence is important to find an effective preventive strategy for AD, which is blocking the formation of Zn-Aβ
in the extracellular compartment.