Cyclophilin D (CypD, encoded by Ppif) is an integral part of the mitochondrial permeability transition pore, whose opening leads to cell death. Here we show that interaction of CypD with mitochondrial amyloid-β protein (Aβ) potentiates mitochondrial, neuronal and synaptic stress. The CypD-deficient cortical mitochondria are resistant to Aβ- and Ca2+-induced mitochondrial swelling and permeability transition. Additionally, they have an increased calcium buffering capacity and generate fewer mitochondrial reactive oxygen species. Furthermore, the absence of CypD protects neurons from Aβ- and oxidative stress-induced cell death. Notably, CypD deficiency substantially improves learning and memory and synaptic function in an Alzheimer's disease mouse model and alleviates Aβ-mediated reduction of long-term potentiation. Thus, the CypD-mediated mitochondrial permeability transition pore is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of Alzheimer's disease. Blockade of CypD may be a therapeutic strategy in Alzheimer's disease.

SummaryThe role of two peptides, Aβ40 and Aβ42 in the early pathogenesis of the Alzheimer's disease (AD) is frequently emphasized in the literature. It is known that Aβ42 is more prone to aggregation than Aβ40, even though they only differ in two (IA) amino acid residues at the C-terminal end. A direct comparison of the ensembles of conformations adopted by the monomers in solution has been limited by the inherent flexibility of the unfolded peptides. Here we characterize the conformations of Aβ40 and Aβ42 in water by using a combination of molecular dynamics (MD) and measured scalar 3 J HNHα data from NMR experiments. We perform replica exchange MD (REMD) simulations and find that classical forcefields quantitatively reproduce the NMR data when the sampling is extended to the microseconds time scale. Using the quantitative agreement of the NMR data as a validation of the model, we proceed to compare the conformational ensembles of the Aβ40 and Aβ42 peptide monomers. Our analysis confirms the existence of structured regions within the otherwise flexible Aβ peptides. We find that the C-terminus of Aβ42 is more structured than that of Aβ40. The formation of a β-hairpin in the sequence 31 IIGLMVGGVVIA involving short strands at residues 31−34 and 38−41 reduces the C-terminal flexibility of the Aβ42 peptide and may be responsible for the higher propensity of this peptide to form amyloids. KeywordsAlzheimer's disease; Amyloid-β peptides; conformational ensemble; replica exchange molecular dynamics; J-coupling constants Two peptides have received tremendous interest in modern Alzheimer's disease (AD) research. Aβ40 and 42 are major products of the proteolytic cleavage of a multi-domain integral membrane type I protein, Amyloid-β Precursor Protein (APP), whose functions include cell adhesion, neuronal mobility and transcriptional regulation 1 . APP metabolism includes processing by a group of dedicated proteases, named secretases, in two known pathways to yield intracellular and extracellular fragments with a broad range of functions in synaptic transmission and neuronal plasticity 2 . During the amyloidogenic pathway, the action of β and subsequently γ secretase yields the Aβ peptides. The exact location of the transmembrane cleavage site for γ secretase results in a variability in the length of its Aβ product from 38 to 43 residues, however lengths of 40 and 42 are the dominant species. The physiological role of the Aβ peptides in vivo remains unclear. Aβ40 has been proposed to regulate the activity of K + channels 3 and also to modulate synaptic transmission 4 , however the mechanisms upon it * To whom correspondence should be addressed angel@rpi.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production p...

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Oxidizing a single M35 residue of Abeta leads to delayed aggregation and reduced toxicity. To understand the molecular mechanism of this effect, we examined the structural and dynamical consequences of M35 oxidation. We found the mobility of the C-terminal residues of Abeta42 is greatly enhanced upon M35 oxidation. In contrast, methyl groups in the central hydrophobic cluster become less flexible. Taken together, we conclude that Abeta42ox undergoes Abeta40-like structural and dynamical changes, which contribute to its reduced aggregation and toxicity.

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