Soluble amyloid beta levels are elevated in the white matter of Alzheimer’s patients, independent of cortical plaque severity

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease and the leading cause of dementia. In addition to grey matter pathology, white matter changes are now recognized as an important pathological feature in the emergence of the disease. Despite growing recognition of the importance of white matter abnormalities in the pathogenesis of AD, the causes of white matter degeneration are still unknown. While multiple studies propose Wallerian-like degeneration as the source of white matter change, others suggest that primary white matter pathology may be due, at least in part, to other mechanisms, including local effects of toxic Aβ peptides. In the current study, we investigated levels of soluble amyloid-beta (Aβ) in white matter of AD patients (n=12) compared with controls (n=10). Fresh frozen white matter samples were obtained from anterior (Brodmann area 9) and posterior (Brodmann area 1, 2 and 3) areas of post-mortem AD and control brains. ELISA was used to examine levels of soluble Aβ -42 and Aβ -40. Total cortical neuritic plaque severity rating was derived from individual ratings in the following areas of cortex: mid-frontal, superior temporal, pre-central, inferior parietal, hippocampus (CA1), subiculum, entorhinal cortex, transentorhinal cortex, inferior temporal, amygdala and basal forebrain. Compared with controls, AD samples had higher white matter levels of both soluble Aβ -42 and Aβ -40. While no regional white matter differences were found in Aβ -40, Aβ -42 levels were higher in anterior regions than in posterior regions across both groups. After statistically controlling for total cortical neuritic plaque severity, differences in both soluble Aβ -42 and Aβ -40 between the groups remained, suggesting that white matter Aβ peptides accumulate independent of overall grey matter fibrillar amyloid pathology and are not simply a reflection of overall amyloid burden. These results shed light on one potential mechanism through which white matter degeneration may occur in AD. Given that white matter degeneration may be an early marker of disease, preceding grey matter atrophy, understanding the mechanisms and risk factors that may lead to white matter loss could help to identify those at high risk and to intervene earlier in the pathogenic process.

Effect of ninjin'yoeito, a Kampo (traditional Japanese) medicine, on cognitive impairment and depression in patients with Alzheimer's disease: 2 years of observation

“…In addition, Collins‐Praino et al . reported that WM Aβ peptides accumulate independently of the overall grey matter fibrillar amyloid pathology . These findings suggest that WM disease might be an early event in the pathogenesis of AD and may support our hypothesis in the current study.…”

“…In the past few years, several studies have reported that soluble Aβ oligomers, rather than insoluble Aβ fibrils, are correlated with the extent of synaptic loss and the severity of cognitive impairment in AD . However, recognition of the importance of WM abnormalities in the pathogenesis of AD has been growing, and AD patients have been shown to exhibit increased WM levels of soluble Aβ, compared with non‐AD controls …”

The metalloprotease ADAMTS4 generates N-truncated Aβ4–x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer’s disease

“…The etiology of white matter lesions in AD is unknown and it has been proposed that oligodendrocyte degeneration occurs mainly secondary to the loss of neurons and axons (so called Wallerian degeneration) [49]. On the other hand, studies have shown that Aβ peptides are cytotoxic to oligodendrocytes and that they accumulate in white matter structures [12,16,32,65,80], raising the possibility that N-truncated Aβ4-x peptides produced by oligodendrocytes or in myelinated axons could be uniquely harmful. This putative pathogenic mechanism should be investigated further, which will likely require new animal models that account for a pro-amyloidogenic role of oligodendrocytes in the pathogenesis of AD.…”

Blood–brain and blood–cerebrospinal fluid passage of BRICHOS domains from two molecular chaperones in mice

“…A delay in amyloid plaque formation and complete absence of cognitive decline were observed when a Bri2-A␤42 fusion protein was used to express A␤42 in the mouse brain (40), suggesting that co-expression of Bri2 BRICHOS alleviates A␤42 neurotoxicity (19). The rh Bri2 BRICHOS concentrations detected in brains after intravenous injection (120 -880 nM) were higher than the soluble A␤40 and A␤42 concentrations reported in different regions of AD postmortem brain tissues (30 -120 pM) (41). A␤42 aggregation is extensively delayed (9), and most importantly, A␤42 toxicity to hippocampal slice preparations is reduced in the presence of substoichiometric concentrations of rh Bri2 BRICHOS (18); we speculate that the amounts of rh Bri2 BRICHOS that reach the brain after parenteral administration could effectively inhibit A␤ fibril formation and toxicity.…”