Increased Aβ Peptides and Reduced Cholesterol and Myelin Proteins Characterize White Matter Degeneration in Alzheimer's Disease

Abstract

Relative to the gray matter, there is a paucity of information regarding white matter biochemical alterations and their contribution to Alzheimer's disease (AD). Biochemical analyses of AD white matter combining size-exclusion, normal phase, and gas chromatography, immunoassays, and Western blotting revealed increased quantities of Abeta40 and Abeta42 in AD white matter accompanied by significant decreases in the amounts of myelin basic protein, myelin proteolipid protein, and 2',3'-cyclic nucleotide 3'-phosphodiesterase. In addition, the AD white matter cholesterol levels were significantly decreased while total fatty acid content was increased. In some instances, these white matter biochemical alterations were correlated with patient apolipoprotein E genotype, Braak stage, and gender. Our observations suggest that extensive white matter axonal demyelination underlies Alzheimer's pathology, resulting in loss of capacitance and serious disturbances in nerve conduction, severely damaging brain function. These white matter alterations undoubtedly contribute to AD pathogenesis and may represent the combined effects of neuronal degeneration, microgliosis, oligodendrocyte injury, microcirculatory disease, and interstitial fluid stasis. To accurately assess the success of future therapeutic interventions, it is necessary to have a complete appreciation of the full scope and extent of AD pathology.

Decreasing myelin density reflected increasing white matter pathology in Alzheimer's disease—a neuropathological study

“…Compared to normal white matter, there was a significantly low myelin density in moderate and severe WMD. In AD, myelin reduction has been shown by neuropathology, biochemical analyses and MRI (Englund and Brun, 1990;Roher et al, 2002;Bartzokis et al, 2003). This is, however, to our knowledge the first time white matter myelin loss in AD has been quantitatively estimated neuropathologically on sections for microscopy.…”

Early Oligodendrocyte/Myelin Pathology in Alzheimer's Disease Mice Constitutes a Novel Therapeutic Target

“…[1][2][3] The underlying cause of the observed white matter changes in early AD brains may relate to compromised function of cells of the oligodendrocyte lineage resulting from disease-related insults. 4,5 Initial AD-related white matter aberrations often precede advanced stages of AD described by overt amyloid and tau pathology. 6,7 The inability of oligodendrocytes to sufficiently myelinate neuronal processes or maintain extant myelin status might render the affected axonal processes vulnerable to disease-related inflammation, oxidative stress, fibrillogenic A␤, or phospho-tau species.…”

Alzheimer’s Disease Pathogenesis: The Denied Access Model

“…Although the gray matter regions are more intensely studied, white matter atrophy occurs in AD [109] and is found in roughly 60% of AD cases [110]. White matter atrophy is often considered secondary to gray matter damage [111], but recent developments determined white matter damage occurs in pre-AD stages and cannot be linked to gray matter atrophy [112,113]. Furthermore, studies analyzing white matter attributed the damage to cognitive decline [114] and discovered higher levels of soluble Aβ in AD patients [115].…”