Cognitive effects of cell-derived and synthetically derived Aβ oligomers.
Soluble forms of amyloid-β peptide (Aβ) are a molecular focus in Alzheimer's disease research. Soluble Aβ dimers (≈8 kDa), trimers (≈12 kDa), tetramers (≈16 kDa) and Aβ*56 (≈56 kDa) have shown biological activity. These Aβ molecules have been derived from diverse sources, including chemical synthesis, transfected cells, and mouse and human brain, leading to uncertainty about toxicity and potency. Herein, synthetic Aβ peptide-derived oligomers, cell- and brain-derived low-n oligomers, and Aβ*56, were injected intracerebroventricularly (icv) into rats assayed under the Alternating Lever Cyclic Ratio (ALCR) cognitive assay. Cognitive deficits were detected at 1.3 μM of synthetic Aβ oligomers and at low nanomolar concentrations of cell-secreted Aβ oligomers. Trimers, from transgenic mouse brain (Tg2576), did not cause cognitive impairment at any dose tested, whereas Aβ*56 induced concentration-dependent cognitive impairment at 0.9 and 1.3μM. Thus, while multiple forms of Aβ have cognition impairing activity, there are significant differences in effective concentration and potency.
Reed
Miranda N
MN
N. Bud Grossman Center, University of Minnesota, Minneapolis, MN 55455, United States.
Hofmeister
Jacki J
JJ
Jungbauer
Lisa
L
Welzel
Alfred T
AT
Yu
Chunjiang
C
Sherman
Mathew A
MA
Lesné
Sylvain
S
LaDu
Mary Jo
MJ
Walsh
Dominic M
DM
Ashe
Karen H
KH
Cleary
James P
JP
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000235:genetics / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D016466:CHO Cells / Q000737:chemistry; D002850:Chromatography, Gel / Q000379:methods; D003072:Cognition Disorders / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D006224:Cricetinae; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D006801:Humans; D007276:Injections, Intraventricular / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D018625:Microscopy, Atomic Force / Q000379:methods; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000235:genetics / Q000633:toxicity*; D017434:Protein Structure, Tertiary; D051381:Rats; D016622:Silver Staining; D014162:Transfection / Q000379:methods
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)