Demyelination in mild cognitive impairment suggests progression path to Alzheimer's disease.

The preclinical Alzheimer's disease (AD) - amnestic mild cognitive impairment (MCI) - is manifested by phenotypes classified into exclusively memory (single-domain) MCI (sMCI) and multiple-domain MCI (mMCI). We suggest that typical MCI-to-AD progression occurs through the sMCI-to-mMCI sequence as a result of the extension of initial pathological processes. To support this hypothesis, we assess myelin content with a Magnetization Transfer Ratio (MTR) in 21 sMCI and 21 mMCI patients and in 42 age-, sex-, and education-matched controls. A conjunction analysis revealed MTR reduction shared by sMCI and mMCI groups in the medial temporal lobe and posterior structures including white matter (WM: splenium, posterior corona radiata) and gray matter (GM: hippocampus; parahippocampal and lingual gyri). A disjunction analysis showed the spread of demyelination to prefrontal WM and insula GM in executive mMCI. Our findings suggest that demyelination starts in the structures affected by neurofibrillary pathology; its presence correlates with the clinical picture and indicates the method of MCI-to-AD progression. In vivo staging of preclinical AD can be developed in terms of WM/GM demyelination

Structure of p300 in complex with acyl-CoA variants

Histone acetylation plays an important role in transcriptional activation. Histones are also modified by chemically diverse acylations that are frequently deposited by p300, a transcriptional coactivator that uses a number of different acyl-CoA cofactors. Here we report that while p300 is a robust acetylase, its activity gets weaker with increasing acyl-CoA chain length. Crystal structures of p300 in complex with propionyl-, crotonyl-, or butyryl-CoA show that the aliphatic portions of these cofactors are bound in the lysine substrate-binding tunnel in a conformation that is incompatible with substrate transfer. Lysine substrate binding is predicted to remodel the acyl-CoA ligands into a conformation compatible with acyl-chain transfer. This remodeling requires that the aliphatic portion of acyl-CoA be accommodated in a hydrophobic pocket in the enzymes active site. The size of the pocket and its aliphatic nature exclude long-chain and charged acyl-CoA variants, presumably explaining the cofactor preference for p300