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S1‐02–06: Strategies to prevent neural network dysfunction in Alzheimer's disease
Author(s) -
Mucke Lennart
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.195
Subject(s) - forebrain , genetically modified mouse , apolipoprotein e , disease , neuroscience , pathological , transgene , medicine , pathogenesis , amyloid (mycology) , amyloid β , long term potentiation , biology , pathology , gene , central nervous system , genetics , receptor
stable low-n oligomers of Abeta reduce synaptic plasticity and number. Here we describe the synaptotoxic properties of Abeta low-n oligomers (principally dimers) isolated from human CSF and aqueous extracts of Alzheimer brain. Methods: Sixty eight CSF samples were tested for the presence of SDS-stable Abeta oligomers using a sensitive IP/Western blot (IP/Wb) protocol. All were found to contain abundant monomer and a fraction (fourteen) were found to contain both Abeta monomer and dimer. Three samples containing monomer alone and six samples containing monomer plus dimer were tested for their effect on LTP in anaethetized Wistar rats. To search for soluble Abeta species in human brain small portions of cortex were homogenized in TBS, spun at 125,000g for 78 min and the supernate analyzed by IP/Wb. Samples containing Abeta dimers were then tested for their effect on LTP and the performance of trained rats in a step-through passive avoidance task. In addition, covalently cross-linked Abeta dimers were generated using synthetic Abeta1-40 in which serine 26 was substituted with cysteine (Abeta1-40Ser26Cys). Disulfide bond formation was achieved by atmospheric oxidation and Abeta dimers were isolated from unreacted monomer and higher aggregates by size exclusion chromatography (SEC). Results: Samples that contained Abeta dimer caused a robust block of LTP, whereas neither concentration-matched samples that contained only Abeta monomer nor Abeta monomer isolated from CSF were capable of altering LTP. Moreover, TBS extracts of human brain that contained SDS-stable Abeta dimers blocked LTP both in vitro and in vivo and dramatically reduced performance in the passive avoidance paradigm. Although these data strongly suggested that A dimers were responsible for impairment of plasticity, there remained the possibility that co-factors present in CSF and brain were also required. To address this possibility, we tested the effect of pure synthetic Abeta1-40 dimer. The synthetic dimer blocked LTP both in vivo and in vitro with a potency at least 20 times greater than freshly dissolved wild type Abeta1-40 or SEC-isolated Abeta1-40Ser26Cys. Conclusions: These results suggest that Abeta dimers are potent synaptotoxins and represent the earliest noxious Abeta assembly in diseased brain.