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Kretner, Benedikt; Trambauer, Johannes; Fukumori, Akio; Mielke, Janina; Kuhn, Peer-Hendrik; Kremmer, Elisabeth; Giese, Armin; Lichtenthaler, Stefan F.; Haass, Christian ORCID: 0000-0002-4869-1627; Arzberger, Thomas; Steiner, Harald (2016): Generation and deposition of A43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's disease. In: Embo Molecular Medicine, Vol. 8, No. 5: pp. 458-465


As stated by the prevailing amyloid cascade hypothesis, Alzheimer's disease (AD) is caused by the aggregation and cerebral deposition of long amyloid- peptide (A) species, which are released from a C-terminal amyloid precursor protein fragment by -secretase. Mutations in its catalytic subunit presenilin-1 (PS1) increase the A42 to A40 ratio and are the major cause of familial AD (FAD). An opposing hypothesis states that loss of essential presenilin functions underlies the disease. A major argument for this hypothesis is the observation that the nearly inactive PS1 L435F mutant, paradoxically, causes FAD. We now show that the very little A generated by PS1 L435F consists primarily of A43, a highly amyloidogenic species which was overlooked in previous studies of this mutant. We further demonstrate that the generation of A43 is not due to a trans-dominant effect of this mutant on WT presenilin. Furthermore, we found A43-containing plaques in brains of patients with this mutation. The aberrant generation of A43 by this particular mutant provides a direct objection against the presenilin hypothesis.