The role of amyloid-ß in white matter damage: possible common pathogenetic mechanisms in neurodegenerative and demyelinating diseases

Just as multiple sclerosis (MS) has long been primarily considered a white matter (WM) disease, Alzheimer's disease (AD) has for decades been regarded only as a grey matter disorder. However, convergent evidences have suggested that WM abnormalities are also important components of AD, at the same extent as axonal and neuronal loss is critically involved in MS pathophysiology since early clinical stages. These observations have motivated a more thorough investigation about the possible mechanisms that could link neuroinflammation and neurodegeneration, focusing on amyloid-ß (Aß). Neuroimaging studies have found that patients with AD have widespread WM abnormalities already at the earliest disease stages and prior to the presence of Aß plaques. Moreover, a correlation between cerebrospinal fluid (CSF) Aß levels and WM lesion load was found. On the other hand, recent studies suggest a predictive role for CSF Aß levels in MS, possibly due in the first instance to the reduced capacity for remyelination, consequently to a higher risk of WM damage progression, and ultimately to neuronal loss. We undertook a review of the recent findings concerning the involvement of CSF Aß levels in the MS disease course and of the latest evidence of AD related WM abnormalities, with the aim to discuss the potential causes that may connect WM damage and amyloid pathology

Description of study sample.

<p>Data are represented as means ± SEM. Mini-Mental-State Examination (MMSE) normal range: 0–30. Activities of Daily Living (ADL) normal range: 0–6.</p

ECS gene expression levels.

<p>ECS genes (panel a: receptors; panel b: metabolic enzymes) expression in PBMCs from LOAD subjects. Bars represent 2^−DDCt values calculated by Delta–Delta Ct (DDCt) method. Expression was normalized to GAPDH, and data are represented as means ± SEM. *p<0.05 <i>vs</i> control.</p

<i>faah</i> DNA methylation levels <i>vs</i> MMSE score.

<p>a: Amount of methylated DNA at <i>faah</i> gene in LOAD subjects subgrouped on the basis of MMSE score; b: Correlation between changes in DNA methylation at <i>faah</i> gene and LOAD subjects with severe AD, based on MMSE score. Data were compared by Pearson's rank correlation coefficient (p<0.05, r = −0.6240).</p

Genetic and epigenetic regulation of <i>faah</i> gene.

<p>a: Levels of FAAH mRNA in PBMCs from LOAD patients (n = 13) and controls (n = 12); b: Amount of methylated DNA at <i>faah</i> gene in controls (n = 33 ) and LOAD subjects (n = 33); c: Correlation between <i>faah</i> gene expression and % change of DNA methylation in LOAD subjects. Data were compared by Spearman's rank correlation coefficient (p<0.05, r = −0.5326). Scatter dots represent 2^−DDCt values calculated by Delta-Delta Ct (DDCt) method, as described in the Materials and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039186#s2" target="_blank">Methods</a> section.</p

Primers used for gene expression and DNA methylation analysis.

<p>Primers used for gene expression and DNA methylation analysis.</p

Levels of FAAH protein and activity.

<p>a: Analysis of FAAH protein levels in PBMCs from LOAD and control (CT) subjects. Values represent means ± SEM, *p<0.05 <i>vs</i> CT. Representative immunoblots of PBMC lysates reacted with specific anti-FAAH or anti-actin antibodies are shown, as well as FAAH immunoreactivity in rat liver extracts and HeLa cell lysates, used as positive and negative controls respectively. Molecular mass markers and the positions of FAAH and actin are indicated to the right. b: FAAH activity in LOAD and CT subjects, expressed as pmol/min per mg of protein (means ± SEM).</p

Baseline characteristics and comorbidities in the whole sample, in stable MCI at follow up and in MCI progressed to dementia.

<p>Baseline characteristics and comorbidities in the whole sample, in stable MCI at follow up and in MCI progressed to dementia.</p

Progression to dementia of MCI subjects divided into three categories of weight change.

<p>Progression to dementia of MCI subjects divided into three categories of weight change.</p

Relative risk of progression from MCI to dementia and Alzheimer's disease in relation to weight change: Cox regression model adjusted for the potential confounding variables in 102 subjects.

<p>Relative risk of progression from MCI to dementia and Alzheimer's disease in relation to weight change: Cox regression model adjusted for the potential confounding variables in 102 subjects.</p