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The levels of water-soluble and triton-soluble A? are increased in Alzheimer's disease brain.

ABSTRACT: Although plaques composed of the amyloid ?-protein (A?) are considered a defining feature of Alzheimer's disease (AD), they are also found in cognitively normal individuals and extensive evidence suggests that non-plaque, water-soluble forms of A? may play a role in AD pathogenesis. However, the relationship between the levels of water-soluble A? and the clinical severity of disease has never been investigated. Here, we present results of a pilot study designed to examine the levels of water-soluble forms of A? in brains of individuals who died at clinically distinct stages of AD. Using a serial extraction method, we also investigated the levels of triton-soluble and formic acid-soluble A?. We found that water-soluble and detergent-soluble A? monomer and SDS-stable dimer were elevated in AD and that the levels of water soluble A? did not increase with plaque pathology. These results support the notion that both water- and detergent-soluble A? are important in AD and are not simply released from plaques by mechanical disruption. Moreover, the fact that the levels of water- and triton-soluble A? were similar in very mild/mild AD and moderate/severe AD suggests that once a certain level of these species is attained, further accumulation is not necessary for the disease to progress. Consequently, therapeutic targeting of water-soluble A? should best benefit individuals in earliest phases of the disease process.

SUBMITTER: McDonald JM

PROVIDER: S-EPMC3319647 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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The levels of water-soluble and triton-soluble Aβ are increased in Alzheimer's disease brain.

McDonald Jessica M JM Cairns Nigel J NJ Taylor-Reinwald Lisa L Holtzman David D Walsh Dominic M DM

Brain research 20120224

Although plaques composed of the amyloid β-protein (Aβ) are considered a defining feature of Alzheimer's disease (AD), they are also found in cognitively normal individuals and extensive evidence suggests that non-plaque, water-soluble forms of Aβ may play a role in AD pathogenesis. However, the relationship between the levels of water-soluble Aβ and the clinical severity of disease has never been investigated. Here, we present results of a pilot study designed to examine the levels of water-sol ...[more]

PMID: 22440675

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Project description:Clusterin, also known as apoJ, is a lipoprotein abundantly expressed within the CNS. It regulates Aβ fibril formation and toxicity and facilitates amyloid-β (Aβ) transport across the blood-brain barrier. Genome-wide association studies have shown variations in the clusterin gene (CLU) to influence the risk of developing sporadic Alzheimer's disease (AD). To explore whether clusterin modulates the regional deposition of Aβ, we measured levels of soluble (NP40-extracted) and insoluble (guanidine-HCl-extracted) clusterin, Aβ40 and Aβ42 by sandwich ELISA in brain regions with a predilection for amyloid pathology-mid-frontal cortex (MF), cingulate cortex (CC), parahippocampal cortex (PH), and regions with little or no pathology-thalamus (TH) and white matter (WM). Clusterin level was highest in regions with plaque pathology (MF, CC, PH and PC), approximately mirroring the regional distribution of Aβ. It was significantly higher in AD than controls, and correlated positively with Aβ42 and insoluble Aβ40. Soluble clusterin level rose significantly with severity of cerebral amyloid angiopathy, and in MF and PC regions was highest in APOE ɛ4 homozygotes. In the TH and WM (areas with little amyloid pathology) clusterin was unaltered in AD and did not correlate with Aβ level. There was a significant positive correlation between the concentration of clusterin and the regional levels of insoluble Aβ42; however, the molar ratio of clusterin : Aβ42 declined with insoluble Aβ42 level in a region-dependent manner, being lowest in regions with predilection for Aβ plaque pathology. Under physiological conditions, clusterin reduces aggregation and promotes clearance of Aβ. Our findings indicate that in AD, clusterin increases, particularly in regions with most abundant Aβ, but because the increase does not match the rising level of Aβ42, the molar ratio of clusterin : Aβ42 in those regions falls, probably contributing to Aβ deposition within the tissue.

Dataset Information

The levels of water-soluble and triton-soluble A? are increased in Alzheimer's disease brain.

Publications

The levels of water-soluble and triton-soluble Aβ are increased in Alzheimer's disease brain.

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