Human brain myelination and amyloid beta deposition in Alzheimer's disease

Abstract

We hypothesized that myelin breakdown in vulnerable late-myelinating regions releases oligodendrocyte- and myelin-associated iron that promotes amyloid beta (A beta) oligomerization, its associated toxicity, and the deposition of oligomerized A beta and iron in neuritic plaques observed in Alzheimer's disease (AD). The model was tested by using published maps of cortical myelination from 1901 and recent in vivo imaging maps of A beta deposits in humans. The data show that in AD, radiolabeled ligands detect A beta deposition in a distribution that matches the map of late-myelinating regions. Furthermore, the strikingly lower ability of this imaging ligand to bind A beta in animal models is consistent with the much lower levels of myelin and associated iron levels in rodents when compared with humans. The hypotheses derived from the "myelin model" are testable with current imaging methods and have important implications for therapeutic interventions that should be expanded to include novel targets such as oligodendrocytes, myelin, and brain iron.

Keywords: Aging; Alzheimer’s disease; Amyloid; Degeneration; Dementia; Iron; Medications; Myelin; Oligodendrocyte; PIB; Prevention; Treatment; White matter.

Fig 1

(A) Amyloid deposition in dark grey, with lighter areas within the dark grey representing progressively more significant changes, as imaged with 11C Pittsburgh Compound-B, displayed in standard space lateral view. Reprinted from Buckner et al [35] with permission. Copyright 2005 by the Society for Neuroscience. (B) Late-myelinating regions in white; lateral brain view corresponds to positron emission tomography (PET)–derived image on the left. Reprinted from Meyer [37] with permission. (C) Amyloid deposition in dark grey, with lighter areas within the dark grey representing progressively more significant changes, as imaged with 11C Pittsburgh Compound-B, displayed in standard space medial view. Reprinted from Buckner et al [35] with permission. Copyright 2005 by the Society for Neuroscience. (D) Late-myelinating regions in white; medial brain view corresponds to PET-derived image on the left. Note: This image is “tilted” to expose the underside of the frontal and temporal lobe regions, which is not the case for the PET image on the left (C), and the exposed underside of those lobes should be ignored when comparing (C) and (D). Reprinted from Meyer [37] with permission.