AUTHOR=Lana Erica , Gellerbring Anna , Jung Sabrina , Nordberg Agneta , Unger Lithner Christina , Darreh-Shori Taher 

TITLE=Homomeric and Heteromeric Aβ Species Exist in Human Brain and CSF Regardless of Alzheimer’s Disease Status and Risk Genotype

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 12 - 2019

YEAR=2019

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2019.00176

DOI=10.3389/fnmol.2019.00176

ISSN=1662-5099

ABSTRACT=Background: A fundamental question in Alzheimer’s disease is whether amyloid-β peptides and their deposition in the brain signify a direct pathological role, or they are mere outcome of the disease pathophysiological events affecting neuronal function. It is therefore important to decipher their physiological role in the brain. So far, the overwhelming focus has been on the potential toxicity of amyloid-β, often studied outside the crucial Alzheimer’s disease characteristics, i.e. i) the slow, decades-long disease progression that precedes clinical symptoms; ii) the link to apolipoprotein-E ε4 allele as major risk factor; iii) the selective early degeneration of cholinergic neurons. Previous studies, in vitro and CSF only, indicated one possible native function of amyloid-β peptides is the allosteric modulation of acetylcholine homeostasis, via molecular interactions between amyloid-β, apolipoprotein-E, and the acetylcholine-degrading enzymes, cholinesterases, resulting in formation of acetylcholine-hydrolyzing complexes (BaβACs).
Methods: Here, by combining sucrose-density gradient fractionation of post-mortem brain and in-house developed sensitive ELISA assays on the obtained fractions, we investigated presence, levels and molecular interactions between amyloid-β, apolipoprotein-E and cholinesterases for the first time in brain tissues. We examined three distinct brain regions of Alzheimer and non-demented subjects, plus a large number of Alzheimer CSF samples.
Results: We report that both monomeric and oligomeric (homomeric and heteromeric) forms of amyloid-β peptides are present in the brain of Alzheimer and non-demented individuals. Heteromeric amyloid-β was found in stable complexes with apolipoprotein-E and/or cholinesterases, irrespective of APOE genotype or disease status, arguing in favor of a physiological dynamic formation and function for these complexes in the brain. The patterns and molecular sizes of the detected soluble amyloid-β forms were closely matched between CSF and brain samples. This evinces that the detected amyloid-β-apolipoprotein-E complexes and BAβACs in CSF most likely originate from the interstitial fluids of the brain.
Conclusions: In conclusion, both light homomeric amyloid-β oligomers and heteromeric amyloid-β -ApoE and BAβACs are present and readily detectable in the brain, regardless of disease status and APOE4 genotype. Deeper knowledge of the physiological function of amyloid-β is crucial for better understanding the early pathological events that decades later lead to manifestation of Alzheimer’s disease.