Alzheimer disease periventricular white matter lesions exhibit specific proteomic profile alterations

CASTAÑO EM; MAAROUF CL; WU; LEAL MC; WHITESIDE CD; LUE LF; BEACH TG; ROHER AE

NEUROCHEMISTRY INTERNATIONAL

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2013 vol. 62 p. 145 - 156

0197-0186

The white matter (WM) represents approximately half the cerebrum volume and is profoundly affectedin Alzheimer?s disease (AD). However, both theWMresponses to AD as well as potential influences of thiscompartment to dementia pathogenesis remain comparatively neglected. Neuroimaging studies haverevealed WM alterations are commonly associated with AD and renewed interest in examining the pathologicbasis and importance of these changes.In AD subjects, immunohistochemistry and electron microscopy revealed changes in astrocyte morphologyand myelin loss as well as up to 30% axonal loss in areas of WM rarefaction when measuredagainst non-demented control (NDC) tissue. Comparative proteomic analyses were performed on pooledsamples of periventricular WM (PVWM) obtained from AD (n = 4) and NDC (n = 5) subjects with bothgroups having a mean age of death of 86 years. All subjects had an apolipoprotein E e3/3 genotype withthe exception of one NDC subject who was e2/3. Urea-detergent homogenates were analyzed using twodifferent separation techniques: 2-dimensional isoelectric focusing/reverse-phase chromatography and2-dimensional difference gel electrophoresis (2D-DIGE). Proteins with different expression levelsbetween the 2 diagnostic groups were identified using MALDI-Tof/Tof mass spectrometry. In addition,Western blots were used to quantify proteins of interest in individual AD and NDC cases.Our proteomic studies revealed that when WM protein pools were loaded at equal amounts of totalprotein for comparative analyses, there were quantitative differences between the 2 groups. Moleculesrelated to cytoskeleton maintenance, calcium metabolism and cellular survival such as glial fibrillaryacidic protein, vimentin, tropomyosin, collapsin response mediator protein-2, calmodulin, S100-P,annexin A1, a-internexin, a- and b-synuclein, a-B-crystalline, fascin-1, ubiquitin carboxyl-terminal esteraseand thymosine were altered between AD and NDC pools.Our experiments suggest that WM activities become globally impaired during the course of AD withsignificant morphological, biochemical and functional consequential implications for gray matter functionand cognitive deficits. These observations may endorse the hypothesis that WM dysfunction is notonly a consequence of AD pathology, but that it may precipitate and/or potentiate AD dementia.